(Ebook) Advances in Biomembranes and Lipid Self-Assembly

Volume 25 by Aleš Igli■, Ana Garcia-Sáez and Michael

Rappolt (Eds.) ISBN 9780128120804, 9780128121832,
0128120800, 0128121831 Pdf Download

https://ebooknice.com/product/advances-in-biomembranes-and-lipid-
self-assembly-volume-25-6614004

★★★★★
4.7 out of 5.0 (85 reviews )

DOWNLOAD PDF

ebooknice.com
 (Ebook) Advances in Biomembranes and Lipid Self-Assembly
Volume 25 by Aleš Igli■, Ana Garcia-Sáez and Michael Rappolt
(Eds.) ISBN 9780128120804, 9780128121832, 0128120800,
0128121831 Pdf Download

EBOOK

Available Formats

■ PDF eBook Study Guide Ebook

EXCLUSIVE 2025 EDUCATIONAL COLLECTION - LIMITED TIME

INSTANT DOWNLOAD VIEW LIBRARY

Here are some recommended products that we believe you will be
interested in. You can click the link to download.

(Ebook) Biota Grow 2C gather 2C cook by Loucas, Jason; Viles, James

ISBN 9781459699816, 9781743365571, 9781925268492, 1459699815,
1743365578, 1925268497

https://ebooknice.com/product/biota-grow-2c-gather-2c-cook-6661374

(Ebook) Advances in Biomembranes and Lipid Self-Assembly Volume 24 by

Aleš Igli■, Chandrashekhar V. Kulkarni and Michael Rappolt (Eds.) ISBN
9780128050743, 0128050748

https://ebooknice.com/product/advances-in-biomembranes-and-lipid-self-
assembly-volume-24-6614002

(Ebook) Advances in Biomembranes and Lipid Self-Assembly, Volume 23 by

Igli■, Aleš; Kulkami, Chandrashekhar V.; Rappolt, Michael ISBN
9780128047156, 9780128050804, 0128047151, 0128050802

https://ebooknice.com/product/advances-in-biomembranes-and-lipid-self-
assembly-volume-23-5431878

(Ebook) SAT II Success MATH 1C and 2C 2002 (Peterson's SAT II Success)

by Peterson's ISBN 9780768906677, 0768906679

https://ebooknice.com/product/sat-ii-success-
math-1c-and-2c-2002-peterson-s-sat-ii-success-1722018
(Ebook) Matematik 5000+ Kurs 2c Lärobok by Lena Alfredsson, Hans
Heikne, Sanna Bodemyr ISBN 9789127456600, 9127456609

https://ebooknice.com/product/matematik-5000-kurs-2c-larobok-23848312

(Ebook) Master SAT II Math 1c and 2c 4th ed (Arco Master the SAT
Subject Test: Math Levels 1 & 2) by Arco ISBN 9780768923049,
0768923042

https://ebooknice.com/product/master-sat-ii-math-1c-and-2c-4th-ed-
arco-master-the-sat-subject-test-math-levels-1-2-2326094

(Ebook) Cambridge IGCSE and O Level History Workbook 2C - Depth Study:

the United States, 1919-41 2nd Edition by Benjamin Harrison ISBN
9781398375147, 9781398375048, 1398375144, 1398375047

https://ebooknice.com/product/cambridge-igcse-and-o-level-history-
workbook-2c-depth-study-the-united-states-1919-41-2nd-edition-53538044

(Ebook) Advances in Planar Lipid Bilayers and Liposomes Volume 21 by

Ales Iglic, Chandrashekhar V. Kulkarni, Michael Rappolt ISBN
9780128021163, 0128021160

https://ebooknice.com/product/advances-in-planar-lipid-bilayers-and-
liposomes-volume-21-5431700

(Ebook) Advances in Planar Lipid Bilayers and Liposomes Volume 22 by

Ales Iglic, Michael Rappolt, Chandrashekhar V. Kulkarni ISBN
9780128028780, 0128028785

https://ebooknice.com/product/advances-in-planar-lipid-bilayers-and-
liposomes-volume-22-5431702
 EDITORIAL BOARD
Dr. Mibel Aguilar (Monash University, Australia)
Dr. Angelina Angelova (Universit
e de Paris-Sud, France)
Dr. Paul A. Beales (University of Leeds, United Kingdom)
Dr. Habil. Rumiana Dimova (Max Planck Institute of Colloids and Interfaces, Germany)
Dr. Yuru Deng (Changzhou University, China)
Prof. Dr. Nir Gov (The Weizmann Institute of Science, Israel)
Prof. Dr. Wojciech Góźdź (Institute of Physical Chemistry Polish Academy
of Sciences, Poland)
Prof. Dr. Thomas Heimburg (Niels Bohr Institute, University of Copenhagen, Denmark)
Prof. Dr. Tibor Hianik (Comenius University, Slovakia)
Dr. Chandrashekhar V. Kulkarni (Centre for Materials Science, University of Central
Lancashire, Preston, United Kingdom)
Prof. Dr. Angelica Leitmannova Liu (USA)
Dr. Ilya Levental (University of Texas, USA)
Prof. Dr. Reinhard Lipowsky (MPI of Colloids and Interfaces, Potsdam, Germany)
Prof. Dr. Sylvio May (North Dakota State University, USA)
Prof. Dr. Philippe Meleard (Ecole Nationale Superieure de Chimie de Rennes, France)
Prof. Dr. Yoshinori Muto (Gifu, Japan)
V. A. Raghunathan (Raman Research Institute, India)
Dr. Amin Sadeghpour (University of Leeds, United Kingdom)
Prof. Kazutami Sakamoto (Chiba Institute of Science, Japan)
Prof. Dr. Bernhard Schuster (University of Natural Resources and Life Sciences, Vienna)
Prof. Dr. P.B. Sunil Kumar (Indian Institute of Technology Madras, India)
Prof. Dr. Mathias Winterhalter (Jacobs University Bremen, Germany)
Academic Press is an imprint of Elsevier
50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States
525 B Street, Suite 1800, San Diego, CA 92101-4495, United States
The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom
125 London Wall, London, EC2Y 5AS, United Kingdom

First edition 2017

Copyright © 2017 Elsevier Inc. All rights reserved.

No part of this publication may be reproduced or transmitted in any form or by any means,
electronic or mechanical, including photocopying, recording, or any information storage and
retrieval system, without permission in writing from the publisher. Details on how to seek
permission, further information about the Publisher’s permissions policies and our
arrangements with organizations such as the Copyright Clearance Center and the Copyright
Licensing Agency, can be found at our website: www.elsevier.com/permissions.

This book and the individual contributions contained in it are protected under copyright by
the Publisher (other than as may be noted herein).

Notices
Knowledge and best practice in this field are constantly changing. As new research and
experience broaden our understanding, changes in research methods, professional practices,
or medical treatment may become necessary.

Practitioners and researchers must always rely on their own experience and knowledge in
evaluating and using any information, methods, compounds, or experiments described
herein. In using such information or methods they should be mindful of their own safety and
the safety of others, including parties for whom they have a professional responsibility.

To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors,
assume any liability for any injury and/or damage to persons or property as a matter of
products liability, negligence or otherwise, or from any use or operation of any methods,
products, instructions, or ideas contained in the material herein.

ISBN: 978-0-12-812080-4
ISSN: 2451-9634

For information on all Academic Press publications

visit our website at https://www.elsevier.com/books-and-journals

Publisher: Zoe Kruze

Acquisition Editor: Poppy Garraway
Editorial Project Manager: Shellie Bryant
Production Project Manager: Magesh Kumar Mahalingam
Cover Designer: Greg Harris
Typeset by SPi Global, India
CONTRIBUTORS

M.-I. Aguilar
Monash University, Clayton, VIC, Australia
B. Burja
University Medical Centre Ljubljana, Ljubljana, Slovenia
Z. Capáková
Centre of Polymer Systems, Tomas Bata University in Zlin, Zlin, Czech Republic

S. Cučnik
University Medical Centre Ljubljana; Faculty of Pharmacy, University of Ljubljana,
Ljubljana, Slovenia
C.E. Conn
School of Science, College of Science, Engineering and Health, RMIT University,
Melbourne, VIC, Australia
C.J. Drummond
School of Science, College of Science, Engineering and Health, RMIT University,
Melbourne, VIC, Australia
A. Flašker
Chemical Institute, Ljubljana, Slovenia
J.F. Hancock
McGovern Medical School, University of Texas Health Science Center, Houston, TX,
United States
P. Humpolı́ček
Centre of Polymer Systems, Tomas Bata University in Zlin, Zlin, Czech Republic
A. Iglič
Laboratory of Biophysics, Faculty of Electrical Engineering, University of Ljubljana,
Ljubljana, Slovenia
I. Junkar
Josef Stefan Institute, Ljubljana, Slovenia
M. Kulkarni
Laboratory of Biophysics, Faculty of Electrical Engineering, University of Ljubljana,
Ljubljana, Slovenia
T.-H. Lee
Monash University, Clayton, VIC, Australia
A. Mazare
Chair of Surface Science and Corrosion, University of Erlangen–Nuremberg, Erlangen,
Germany

ix
x Contributors

T.G. Meikle
School of Chemistry, Bio21 Institute, University of Melbourne, Melbourne, VIC, Australia
M. Mozetič
Josef Stefan Institute, Ljubljana, Slovenia
K. Mrak-Poljšak
University Medical Centre Ljubljana, Ljubljana, Slovenia
M. Rappolt
School of Food Science and Nutrition, University of Leeds, Leeds, United Kingdom
A. Sadeghpour
School of Food Science and Nutrition, University of Leeds, Leeds, United Kingdom
P.B. Santhosh
Indian Institute of Technology, Chennai, India
D. Sanver
School of Food Science and Nutrition, University of Leeds, Leeds, United Kingdom
P. Schmuki
Chair of Surface Science and Corrosion, University of Erlangen–Nuremberg, Erlangen,
Germany
F. Separovic
School of Chemistry, Bio21 Institute, University of Melbourne, Melbourne, VIC, Australia
S. Sodin-Semrl
University Medical Centre Ljubljana, Ljubljana; Faculty of Mathematics, Natural Science
and Information Technologies, University of Primorska, Koper, Slovenia
S. Sudhakar
Centre for Biotechnology, Anna University, Chennai, India
M. Tomšič
University Medical Centre Ljubljana; Faculty of Medicine, University of Ljubljana,
Ljubljana, Slovenia
Y. Zhou
McGovern Medical School, University of Texas Health Science Center, Houston, TX,
United States
P. Žigon
University Medical Centre Ljubljana, Ljubljana, Slovenia
PREFACE

A combination of chapters covering fundamental aspects of membrane orga-

nization and current concepts for membrane- and lipid-based technologies
are included in Volume 25 of Advances in Biomembranes and Lipid
Self-Assembly (ABiLSA). With a focus on the applied aspects of lipids and
biomembranes, Volume 25 not only covers the exploitation of the rich vari-
ety in lipid phases for encapsulation of biomolecules but also cutting-edge
methods to characterize biomembranes and the effect of peptides and pro-
teins on their organization. From the basic biology side, the molecular
mechanism of Ras at the plasma membrane is covered, as an example of
membrane lateral compartmentalization in protein–lipid assemblies with a
role in signal transduction and cellular function. At the technological end,
the major parameters affecting the compatibility of nanotubes at the interface
with the plasma membrane of adhering cells for the improvement of vascular
implants are discussed. Also at the interface between material sciences and
biological systems, gold nanomaterials offer new possibilities for diagnosis
and as therapeutic agents, for example, the treatment of cancer or in drug
delivery. Along these lines, the encapsulation of peptides and proteins in
cubic phase systems as well as flavonoids in self-assembled lipid mesophases
as delivery systems for biomedical applications are considered. All this would
not be possible without the appropriate tools to characterize the organiza-
tion of lipids in membranes. Differential polarization interferometry offers a
label-free approach to quantify changes in molecular mass and packing order
in membranes.
We would like to thank all authors that contributed to Volume 25:
Snezna Sodin-Semrl, Yong Zhou, Frances Separovic, Amin Sadeghpour,
Mibel Aguilar, Poornima Budime Santhosh, and their coauthors. We are
also grateful to Shellie Bryant and Poppy Garraway from the Elsevier Office
in London, to Magesh Mahalingam from the Elsevier Office in Chennai,
and to all members of the Editorial Board that contributed to the preparation
of this volume of ABiLSA.
ALEŠ IGLIČ
ANA J. GARCIA-SÁEZ
MICHAEL RAPPOLT

xi
 CHAPTER ONE

Could Titanium Dioxide

Nanotubes Represent a Viable
Support System for Appropriate
Cells in Vascular Implants?
I. Junkar*, M. Kulkarni†, P. Humpolíček{, Z. Capáková{, B. Burja§,
A. Mazare¶, P. Schmuki¶, K. Mrak-Poljšak§, A. Flašker||, P. Žigon§,


S. Cučnik §,#
, M. Mozetič*, M. Tomšič§,**, A. Iglič†, S. Sodin-Semrl§,††,1
*Josef Stefan Institute, Ljubljana, Slovenia
†
Laboratory of Biophysics, Faculty of Electrical Engineering, University of Ljubljana, Ljubljana, Slovenia
{
Centre of Polymer Systems, Tomas Bata University in Zlin, Zlin, Czech Republic
§
University Medical Centre Ljubljana, Ljubljana, Slovenia
¶
Chair of Surface Science and Corrosion, University of Erlangen–Nuremberg, Erlangen, Germany
jj
Chemical Institute, Ljubljana, Slovenia
#
Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
**Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
††
Faculty of Mathematics, Natural Science and Information Technologies, University of Primorska, Koper,
Slovenia
1
Corresponding author: e-mail address: [email protected]

Contents
1. Introduction 2
2. Selected Clinical Conditions Associated With Vessel Implants 3
2.1 Atherosclerosis 4
2.2 Coronary Heart Disease 5
2.3 Carotid Artery Disease 5
2.4 Peripheral Artery Disease 6
2.5 Atherosclerotic Renovascular Disease 6
3. Types of Vascular Implants 6
3.1 Stents 7
3.2 Grafts 8
3.3 Stent–Graft 9
3.4 Complications Connected With Stenting Procedures 9
4. Nanotopography, Surface Modifications, and Biocompatibility of Implants 11
5. TiO2 Nanotubes 14
5.1 Growth of TiO2 Nanotubes 15
5.2 Surface Properties of TiO2 Nanotubes 16
6. Surface Modification of TiO2 Nanotubes 19
6.1 Gaseous Plasma: Its Prospective Use in Medical Applications 19
6.2 Gaseous Plasma Treatment of TiO2 Nanotubes 21

Advances in Biomembranes and Lipid Self-Assembly, Volume 25 # 2017 Elsevier Inc. 1

ISSN 2451-9634 All rights reserved.
http://dx.doi.org/10.1016/bs.abl.2016.12.001
2 I. Junkar et al.

6.3 Surface Analysis of Plasma-Modified TiO2 Nanotubes 22

7. Interaction of TiO2 Nanotubes With Cells 22
7.1 Platelets 23
7.2 Endothelial Cells 27
7.3 Mesenchymal Stem Cells 30
8. Antiinfective Properties of TiO2 Nanotubes 32
9. Concluding Remarks and Perspectives 33
References 34

Abstract
Nanoscale topography on various titanium surfaces has already been shown to improve
vascular response in vitro. To propose a novel strategy for translation into clinically used
vascular implants, it is imperative that the surface should also be properly conditioned
to provide a better environment for adhesion and proliferation of cells. Electrochemical
anodization process is one of the well-established strategies to produce controlled
nanotopographic features on the surface of titanium. By combining electrochemical
anodization process and gaseous plasma surface modification, it would be possible
to fine-tune surface properties to enable improved biological response for specific appli-
cation. The key surface properties that may influence biological responses, such as sur-
face topography, surface chemistry, and surface wettability were studied in detail and
their influences on in vitro biological responses were evaluated. Performance of plate-
lets, human coronary artery endothelial cells (HCAEC), and stem cells on those surfaces
was studied. It was shown that altering nanotube diameter (electrochemical anodiza-
tion) and changing surface chemistry and wettability (gaseous plasma modification) sig-
nificantly influenced platelet adhesion and activation as well as proliferation of HCAEC.
The results provide evidence that by combining specific nanotopographic features and
surface chemical modification by gaseous oxygen plasma, the optimized surface fea-
tures necessary for improved performance of vascular implants in coronary arteries
could be achieved.

1. INTRODUCTION
The cardiovascular implant market is expanding rapidly due to pop-
ulation aging in developing countries, with a growing incidence of chronic
and cardiovascular diseases (CVDs) on one side and technological advance-
ment with limited biological replacement options available on the other
side. The basic function of a vascular implant (either grafts or stents) is to
function as an artificial conduit or substitute for an abnormality in veins
or arteries [1]. The durability and functionality of long-term implanted med-
ical devices are influenced by many factors, among them the type of afflic-
tion or injury, the materials used, the immunological state of the patient, and
TiO2 Nanotubes Represent a Viable Support System 3

the healing process itself. The quality of the materials relies largely on their
ability to mimic the structure and properties of the native vessel wall and
tissue. To date, the ability to match the attributes of a vascular substitute
to those of a native vessel still remains a challenge [1] and further develop-
ment is needed in the field of biocompatibility to shape future innovations.
In the following sections, we will address the role of atherosclerosis (ASc),
the major precursor of CVDs, and discuss a selected group of clinical compli-
cations that can occur in different vascular regions. Selected emphasis will be
placed on coronary heart disease (CHD), carotid artery disease (CAD),
peripheral artery disease (PAD), and atherosclerotic renovascular disease
(ARVD), with focus on conditions ranging from stenosis, occlusions, aneu-
rysms to ruptures. Next, we will investigate when and why grafts and stents are
chosen as preferred types of vascular implants. Biomaterials will be discussed,
as well as nanotopography leading to the use of titanium and titanium dioxide
(TiO2) for implants. Treatment of TiO2 nanotubes will be explored from the
biophysical and biochemical aspects, as well as the potential consequences of
treatment on cellular growth of platelets, coronary artery endothelial cells,
and mesenchymal stem cells (MSCs). Lastly, we will focus on the antiinfective
properties of TiO2 vascular implants and propose future directions.

2. SELECTED CLINICAL CONDITIONS ASSOCIATED

WITH VESSEL IMPLANTS
The circulatory system is a complex network responsible for supplying
the organism with nutrients and oxygen, while at the same time removing
metabolic waste products. It is the first organ system to form and function dur-
ing the development of the vertebral embryo [2], which indicates its impor-
tant role. There are numerous different internal and external (genetic and
environmental) factors than can alter vessel integrity and interfere with appro-
priate blood supply to tissues throughout the body. Major risk factors for
developing CVD encompass smoking, diabetes, physical inactivity,
unhealthy diet, cholesterol, obesity, increasing age, autoimmune diseases,
hypertension, infections, gender, and a family history of vascular disease,
among others [3]. They may also lead to early development of atherosclerotic
plaques, complications which can bring about CVD pathogenesis, rep-
resenting the leading cause of morbidity, and mortality in the Western world
[4]. In 2006, CVD cost the health care systems within the EU just under €110
billion. The cost of inpatient hospital care for patients with CVD accounts for
about 54% of these costs, while the cost of drugs accounts for about 28% [1].
4 I. Junkar et al.

2.1 Atherosclerosis
ASc is the underlying pathology of CVD and events leading up to implant
replacement therapy. It is defined as a focal, inflammatory fibro-proliferative
response to multiple forms of endothelial injury [2]. It is a degenerative con-
dition [3], characterized by the presence of intimal lesions called atheroma.
Atheromatous plaques are raised lesions composed of soft lipid cores (mainly
cholesterol along with cholesterol esters and necrotic debris) covered by
fibrous caps [4]. ASc represents a chronic disease, with atherosclerotic
plaques developing slowly over decades. The clinical outcomes (or conse-
quences) of this process depend on the size of the affected vessel and most
importantly, the stability of the plaques. Stable plaques (constituting of dense
fibrous cap, minimal lipid accumulation, and little inflammation) [4] are
associated with vessel occlusion (blockage) and inadequate blood flow to
organs from the affected artery. As a consequence, there is a loss of the ability
to respond with increased blood flow through the fixed artery lumen, most
dangerously observed in coronary arteries. In patients with chronic occlusive
disease, one can detect vessels adapting to this condition by forming new
vessels or collateral circulation. Chronic occlusion will not change resting
blood flow until lumen is largely blocked. Patients will develop symptoms
of blood flow restriction in supplying blood to tissues, which is first noted
under conditions of stress [5]. ASc also predisposes a person to aneurysm for-
mation (widening of an artery due to destruction of the arterial wall). These
aneurysms may favor the formation of blood clots that can break off and
block vessels downstream, or they may burst and hemorrhage, which
may be fatal [5]. In addition to occlusion and aneurysm formation, aortic
dissection is a condition with the most abrupt onset, and if untreated,
may be rapidly fatal [6]. Compared to other clinical manifestations, ASc is
not the major factor promoting aortic dissection, but hypertension, connec-
tive tissue disorders, and injuries are factors that can promote a tear in the
weak intimal layer of the aorta, resulting in a separation of the layers of
the aortic wall (aortic dissection). The vast majority of aortic dissections
originate with an intimal tear in either the ascending aorta (65% of the cases),
the aortic arch (10%), or just distal to the ligamentum arteriosum in the des-
cending thoracic aorta (20%) [7].
ASc individual plaques vary greatly in composition and acute manifesta-
tions of ASc can also occur. Vulnerable or unstable fibrolipid plaques (thin
cap, large lipid cores, and dense inflammatory infiltrates) [4] can rupture and
expose highly thrombogenic, red blood cell-rich necrotic core material
TiO2 Nanotubes Represent a Viable Support System 5

resulting in a cascade of inflammatory events [8]. This may lead to thrombus

formation and platelet aggregation that can cause a complete obstruction of
the arterial lumen and ultimately, myocardial infarction, or ischemic stroke
in the brain.
ASc can affect any artery in the body, but most commonly large elastic
arteries (aorta, carotid, and iliac artery) and large/medium-sized muscular
arteries (carotid, coronary, renal, and popliteal artery) [4] are altered. Con-
sequently, any organ in the body can be involved, but most likely symptom-
atic disease is confined to the arteries supplying the heart, brain, lower limbs,
and kidneys. Depending on which arteries are affected, different diseases,
such as CHD, CAD, PAD, or ARVD may develop. Myocardial and cerebral
infarction, aortic aneurysm, and PAD are by far the most important, clini-
cally significant consequences of ASc [4,9].

2.2 Coronary Heart Disease

In patients with CHD, atherosclerotic plaques build up in the coronary
arteries, thus reducing blood flow to the heart. Fixed obstructions that block
more than 70% of a vessel lumen may cause stable angina pectoris, with
symptoms observed only under conditions of stress. In acute coronary syn-
drome, vulnerable plaque ruptures and thrombus formation may cause com-
plete vessel obstruction and consequently, tissue necrosis (myocardial
infarction).
In the past, the predominant surgical treatment of diseased coronary
arteries was bypass surgery, where the affected artery is “bypassed,” for
example using a vein graft removed from the leg of the patient to divert
blood around the blockage [10]. Considering all the possible complications
of this surgery, more recently, cardiologists have resorted to using minimally
invasive medical devices to “open up” blocked blood vessels. For certain
patients with stable, as well as unstable coronary disease, rapid percutaneous
coronary intervention with stent placement in the occluded artery, along
with appropriate therapy, is the optimal treatment strategy.

2.3 Carotid Artery Disease

Plaques may build up in the carotid arteries, generally supplying oxygen-rich
blood to the neck and brain. The developing plaques can be either stable
(asymptomatic) or symptomatic, when ischemic complications (reduced
blood flow to tissues or organs) emerge with acute blockage of the carotid
artery. If a clot breaks off an atherosclerotic plaque, emboli can travel
6 I. Junkar et al.

through the circulation to blood vessels in the brain. As the vessels become
smaller, the clots can lodge in the vessel wall and restrict blood flow to parts
of the brain. Ischemia (reduced blood flow to tissues or organs) can either be
temporary, yielding a transient ischemic attack (TIA), or permanent,
resulting in a thromboembolic stroke. Treatment of asymptomatic and
symptomatic patients still remains debatable. Revascularization with carotid
endarterectomy (surgical procedure to open and clean a carotid artery) has
proven to be most beneficial for patients with large stenosis or narrowing of
the blood vessel. However, for certain subgroups (patients with moderate
stenosis and high surgical risk) carotid artery stenting has been proposed,
as a less invasive alternative to surgery [11].

2.4 Peripheral Artery Disease

Patients with PAD experience a narrowing of the peripheral arteries most
frequently in the lower extremities. Symptoms are muscle pain, numbness,
cramps, generally in the calf muscle, which occur during walking and can be
relieved by a period of rest. Critical limb ischemia is a manifestation of PAD
that describes patients with chronic ischaemic rest pain or patients with
ischaemic skin lesions, ulcers, and/or nonhealing wounds that can lead to
tissue death or gangrene. In certain cases, this requires amputation of the
affected limbs. Percutaneous revascularization stenting has generally rep-
laced invasive surgery as the first-line treatment for PAD [12].

2.5 Atherosclerotic Renovascular Disease

ARVD may develop following plaque formation in the renal arteries causing
stenosis. Plaque accumulation may lead to decreased kidney blood flow and
renovascular hypertension. Later, chronic kidney disease can develop,
which is typically asymptomatic until late stages. Renal artery stent revascu-
larization can represent a treatment of choice for patients with hemodynam-
ically significant stenosis with progressive renal insufficiency and/or
deteriorating arterial hypertension [12,13].

3. TYPES OF VASCULAR IMPLANTS

There are different types of vascular implants, such as stents, grafts, or a
combination of both.
TiO2 Nanotubes Represent a Viable Support System 7

3.1 Stents
A stent (defined as a tubular metal mesh) is a scaffolding device used to hold
tissue in place in a specific stretched or taut position. In Fig. 1, a vascular stent
and its surface morphology is presented as observed by scanning electron
microscopy. Modern intravascular stents are available in balloon-expandable
and self-expanding varieties [14]. The procedure that leads to the placing of a
stent is called angioplasty and it involves mechanical widening of a narrowed
blood vessel with a balloon catheter that forces the expansion of the vessel
and the surrounding muscular wall. Thus, the blood vessel acquires
improved flow. The stent may or may not be inserted at the time of balloon-
ing to ensure that the blood vessel remains open. In many cases, the deliv-
ered stent becomes permanently implanted to provide additional support to
the artery.
Vascular stents have been indicated to be predominantly metal structures
inserted into partially clogged arteries to promote normal blood flow and
prevent myocardial infarctions [15]. Usually stents are made of hemo-
compatible and durable material, such as Titanium (Ti), 316L stainless steel
(SS-medical grade), Nitinol (an alloy of Nickel and Titanium), and
Cobalt-Chromium (CoCr). In some instances, a stent can elicit allergic reac-
tions most commonly with Nickel, such as Nitinol and stainless steel [16].
In 2013, Acton (Ed.) [17] has described and quoted that coronary angio-
plasty or coronary percutaneous intervention is a therapeutic procedure to
treat stenotic coronary artery, in case of severe angina pectoris or myocardial
infarction. Peripheral angioplasty refers to the use of mechanical widening to
open blood vessels other than the coronary arteries. This procedure is

Fig. 1 Example of a vascular stent (left) and scanning electron microscopy (SEM) image
(right) of its surface.
8 I. Junkar et al.

referred to as percutaneous transluminal angioplasty (PTA), most commonly

used to treat narrowing in the leg arteries (common iliac, external iliac,
superficial femoral, and popliteal arteries). PTA can also be used to treat
narrowing of the veins. In addition, atherosclerotic obstruction of the renal
artery and carotid artery can also be treated with angioplasty. Any of these
procedures can include placement of a stent to prevent or counteract con-
striction of localized blood flow. A stent is typically inserted through a main
artery in the groin (femoral artery) or arm (brachial artery) on a wire or cath-
eter and extended up to the narrowed section of the vessel. Once in place,
the stent can help hold the vessel open, thus improving blood flow [17].

3.2 Grafts
Surgical procedures also include using grafts, in which one or more blocked
arteries are bypassed by a blood vessel graft in order to restore normal blood
flow. The purpose of bypass grafting is to supply blood to distal circulation
beyond the significant stenosis, using a graft which is made of biological
materials (usually patients’ own venous or arterial conduits) [18] or synthetic
materials. Wherever possible, replacement of the diseased blood vessel by an
autograft is the best choice. Unfortunately, patients with preexisting vascular
diseases usually do not have healthy enough blood vessels that could ade-
quately replace the diseased parts. It needs to also be emphasized that some
replacement parts, such as the aorta or large vessels, are not available. There-
fore artificial materials, such as Dacron (PET—polyethylene terephthalate)
or ePTFE (expanded polytetra fluoroethylene) are used as replacements. In
Fig. 2, the two types of Dacron and ePTFE vascular grafts are presented.

Fig. 2 Vascular grafts made from polyethylene terephthalate (left, a) and expanded
polytetrafluoroethylene (right, b).
TiO2 Nanotubes Represent a Viable Support System 9

Both materials have a through-pore microporous wall structure and are

highly flexible, which enables easy implantation in the body. Such materials
have successfully replaced diseased blood vessels of larger diameter, while in
the case of smaller diameter vascular grafts (<5 mm) problems are com-
monly observed, primarily due to thrombosis [19]. Much work has been
conducted to improve surface properties of vascular grafts mainly by coating
the surface with various biomolecules, and vascular grafts coated with
heparin, gelatin, collagen, etc., are commercially available. Most common
bypass sites include coronary vessels in the heart (coronary artery bypass
surgery) and lower extremities to treat peripheral vascular disease.

3.3 Stent–Graft
In certain specific cases, stent–graft combinations may be used. Stent–grafts
or covered stents are composed of a metallic frame (stent) covered either by
native venous grafts or by synthetic materials sewn into the inner or outer
part of the metallic stent frame. These devices can be used in instances, such
as large vessel injuries and aneurysms [20]. Endovascular stent-grafting or
endovascular aneurysm repair is a newer form of treatment for abdominal
aortic aneurysm that is less invasive than open surgery. Endovascular
stent-grafting is now also being considered as an alternative to surgery in aor-
tic dissection, mostly in stable patients with dissections of the descending
aorta [21].

3.4 Complications Connected With Stenting Procedures

According to the World Health Organization 17.3 million people died
because of CVD in 2008. By 2030, the number is projected to reach 23.3
million. Thus the market for manufacturers of vascular stents is predicted
to grow rapidly in the next years [22]. However, stenting procedures are still
not optimal and the constant contact of vascular stents with blood has been
the source of several unresolved efficacy issues [23,24]. For example, con-
ventional bare-metal stents (BMS) often trigger an inflammatory response
leading to scar tissue formation, known as restenosis, which constricts blood
flow defeating the original purpose of the stent [24]. Drug-eluting stents
(DES) counteract such events by releasing an immunosuppressant, however
this immunosuppressant can also suppress desirable endothelial cell (EC)
growth and sometimes lead to late-stage thrombosis [24,25]. First-generation
stents, or BMS, were designed with purely mechanical functionality.
Patients suffering from restenosis (build up of vascular smooth muscle cells
10 I. Junkar et al.

(SMCs) inside the intima that can lead to lumen narrowing) may have a prob-
lem with stent surfaces. The problem occurs in more than 33% of the cases,
with higher possibilities in patients with high risk factors, such as diabetes.
A new-generation DES was developed to overcome stent-connected com-
plications. With DES, the problems of allergenic reactions as well as risks of
restenosis were lowered, as DES release anticell proliferative, immunosup-
pressive, or antithrombogenic drugs which inhibit proliferation of SMCs
and reduce thrombus formation. During stenting, there are two main factors
that can lead to restenosis [26]. When the balloon is opened and pushes back
the plaque in the walls, it can damage the artery wall [27], so the artery can
react to the stent in perceiving it as a foreign body and elicit an immune system
response. In regard to the former, damage to the blood vessel wall by angio-
plasty triggers a physiological response that can be divided into two stages. The
first stage occurs immediately after tissue trauma and can lead to thrombosis.
A blood clot forms at the site of damage and further hinders blood flow. This is
accompanied by an inflammatory immune response. The second stage is the
result of proliferation of SMCs in the intima. In response to vascular trauma,
growth factors are produced that stimulate SMCs to start dividing, with 90%
of the final intimal proliferation being produced in the first 2 weeks, as the
SMC numbers can greatly increase within that period [28]. As the SMCs mul-
tiply, they push through the openings in the stent mesh and cause a narrowing
in the stent lumen. This is also known as neointimal hyperplasia. All this leads
to the remodeling of the vessel and restenosis. One of the factors thought to
initiate stent thrombosis is incomplete endothelialization. Since the drugs
delivered are not target cell specific, they prevent a healthy layer of EC from
forming, thus delaying healing and increasing the potential for thrombogenic
stimulus.
A consideration that should be taken into account is the fact that a typical
stent recipient will often need other surgeries, requiring them to cease the
anticoagulants during that time, and opening the potential for thrombosis to
occur. Owing to the issues also present with DES, several studies [29] are
now looking for other ways of addressing restenosis and the hyper-
proliferation of vascular SMCs by promoting rapid reendothelialization over
the stent. It has been shown [30–33], that there is an inverse relationship
between the luminal EC coverage and the vascular SMC proliferation after
arterial injury. A study by Asahara et al. [34] delivered vascular endothelial
growth factor (VEGF) in order to stimulate endothelial growth after
balloon-induced arterial injury using a rat model system. The effects were
monitored with immunostaining for proliferating cell nuclear antigen
TiO2 Nanotubes Represent a Viable Support System 11

(PCNA). It was reported that the rapid reendothelialization was linked to

the suppression of neointimal hyperplasia, since the VEGF-treated group
had less intimal thickening than those untreated. Moreover, this is supported
by the observation that most of the intimal proliferative activity
(PCNA-positive cells) is concentrated in nonendothelialized regions in both
the treated and untreated (control) animal groups. As such, this provides an
opportunity to explore a new stent paradigm, not reliant on pharmacological
means, to address restenosis through promoting reendothelialization and
healing.
For the above reasons, this chapter deals with the design, synthesis, and
investigation of new TiO2-based biomimetic surfaces, which, by appropri-
ate gaseous plasma treatment enhance EC adhesion and proliferation, while
reducing platelet adhesion and activation. It will be shown that
nanotopographic features influence cell–surface interactions and that final
gaseous plasma conditioning of the surfaces significantly influences platelet
adhesion and activation.

4. NANOTOPOGRAPHY, SURFACE MODIFICATIONS,

AND BIOCOMPATIBILITY OF IMPLANTS
The presence of nanotopography in the body inspired the idea of the
stent surface patterning to form a biomimetic surface that would facilitate
healing by obtaining a layer of EC on the stent. Nanoscale topographical
features are prevalent throughout the body and the basement membranes
of many tissues, which interact directly with adjacent cells. These tissues
are comprised of a complex mixture of nanoscale pores, ridges, and fibers.
For example, the extracellular matrix of human bones is composed of
nanostructured hydroxyapatite particles and collagen nanofibers. Thus, by
appropriate surface nanotopography enhanced cell–surface interactions
and increased osteoblast adhesion, improved osteointegration could be
achieved. Nanopatterning is used in biological research largely due to the
“smaller, faster, cheaper” technology. Topographies with a dimensional
range similar to the cellular environment are now possible, and features with
dimensions below 100 nm are now emerging in biological applications
[35–37]. In vitro results show that surface features on the nanometer scale
indeed stimulate and control several molecular and cellular events taking
place on the biomaterial surface. Differences in cell morphology, orienta-
tion, cytoskeleton organization, proliferation, and gene expression on nano-
structured surfaces compared to flat or microrough surfaces can be observed
12 I. Junkar et al.

[37,38]. For example, nanostructuring of a metallic surface by hydrothermal

treatment was shown to improve endothelialization and, at the same time,
reduce SMC proliferation [38]. Similarly, hydrothermal treatment of tita-
nium wires was employed to produce nanotopography which, under static
and dynamic conditions, showed negligible hemolysis, as well as inhibited
activation and aggregation of platelets. Moreover, the endothelium formed
on nanostructured surfaces had enhanced expression of antithrombogenic
genes, providing for a longer coagulation cascade, probably due to a thicker
oxide layer, in addition to topography [37].
Many factors need to be considered in regard to the application of the
biomedical device, depending on the intended implant location. For exam-
ple, if the biomedical device is intended to be a blood-contacting device
(stent, graft, or catheter), blood compatibility (hemocompatibility) of the
biomaterials is crucial. For such types of applications, the host response
and its severity are strictly related to the surface properties of the biomaterial.
Biomedical devices for use in contact with blood must not activate the
intrinsic blood coagulation system, nor attract/alter platelets or leukocytes.
From this point of view, biocompatibility is more difficult to achieve as it
covers aspects such as thrombogenicity, complement activation, leukocyte
activation, and changes in plasma proteins [39].
It is evident that the response of a biomaterial depends extensively on its
biocompatibility and surface properties. Therefore, in order to improve the
performance of biomaterials in biological systems, there is an urgent need for
their surface modification [40–46]. Nowadays, the most common method of
improving biocompatibility is by modification of the implants’ surface prop-
erties, either by morphologically or by biochemical coatings, or both. Such
surface modification of implants allows for the increase in native tissue adhe-
sion, implant integration, and at the same time, decrease of bacterial adhe-
sion and inflammatory response and/or avoiding the foreign body response
[41,44,47–49]. In order to improve the biological, chemical, and mechanical
properties of biomaterials, significant research has been aimed at finding
more suitable biomaterials with appropriate nanotopography, which could
offer improved bioperformance [47,50]. Increasing capabilities to produce
various nanostructured materials and to study cell–substrate interactions
offer immense potential in development of medical devices [47,50–53].
Some of the common features studied include grooves, pits, posts, and ran-
domly rough features. Through these studies researchers found that cells
had a wide array of responses to topography, which depend on many factors
including cell type, feature size, and geometry, and the physical properties of
TiO2 Nanotubes Represent a Viable Support System 13

the materials. It is the latter that directs our focus to titanium (Ti), due to its
corrosion resistant TiO2 surface layer, making it suitable for contact with
blood, as well as its track record for biocompatibility in prosthetics and dental
implants [46,47,54]. In the last decade, electrochemical anodization was fre-
quently employed, since by using this method, highly oriented TiO2
nanotubes can be formed by electrochemical oxidation of metallic titanium
or other titanium alloys under self-organizing anodization condi-
tions [47,55,56]. By tailoring the anodization parameters (e.g., applied volt-
age, anodization time) and subsequent treatments, TiO2 nanotubes with
different morphologies (diameters, lengths, smoothness of tube wall, bamboo,
multilayers, etc.) can be obtained [55–57]. The excellent potential of titanium
nanotubes in medicine and biotechnology, as well as other applications, is
mainly due to its high surface to volume ratio, the good control over nan-
otopography and the possibility to form specific geometry nanostructures spe-
cially designed to fit the desired biological applications. Moreover, TiO2
nanotubes have been shown to increase selective protein adsorption and sub-
sequently, increase biological responses; for example, many studies showed
that TiO2 nanotubes increase protein adhesion, bone growth/regeneration,
are antibacterial and reduce inflammation [35,51,58–60].
Irrespective of the location of the implant (blood contacting, orthopedic,
or dental implant), the first step that takes place after implantation is the
adsorption of proteins from the surrounding tissue or medium. The amount
and type of protein adsorbed further influences the fate of the implant.
Gongadze et al. [61] proposed a mechanism for the adhesion of cells to a
nanorough titanium implant surface with sharp edges. The basic assumption
was that the attraction between the negatively charged titanium surface and a
negatively charged osteoblast is mediated by charged proteins, with a dis-
tinctive quadrupole internal charge distribution. Similarly, cation-mediated
attraction between fibronectin molecules (present in the extracellular
matrix) and the titanium surface is expected to be more efficient for a high
surface charge density, resulting in facilitated integrin-mediated osteoblast
adhesion. Osteoblasts could be more strongly bound along the sharp convex
edges or spikes of nanorough titanium surfaces, where the magnitude of the
negative surface charge density is the highest. It is therefore plausible that the
nanorough regions of titanium surfaces with sharp edges and spikes could
promote the adhesion of osteoblasts. A small diameter nanotube surface
has on average more sharp convex edges per unit area than a large one,
leading to a strong binding affinity on the surface of small diameter
nanotubes [61].
14 I. Junkar et al.

Herein, we discuss progress toward realization of next-generation

titanium (Ti) stents that seek to mitigate adverse physiological responses
to stenting via rational design of stent surface topography at the nanometer
scale to form a biomimetic surface and to further improve surface properties
by gaseous plasma surface treatment. To better understand the influence of
surface nanotopography on cells, nanotubes with different diameters were
fabricated and in vitro biological responses of EC, stem cells, and platelets
were studied. TiO2 nanotubular surfaces with various diameters were
chosen for these studies due to their relevance for implantable device appli-
cations, as they offer comparatively more surface area and focal adhesion
points [47,61]. We show that nanotube size plays an important part in
the cellular response and that by surface conditioning by gaseous plasma,
improved adhesion and proliferation of EC, and lower adhesion and
activation of platelets can be obtained. These results suggest a promising
and intriguing pathway for nanometer topographic patterning to enhance
endothelialization and neovascularisation for implantable device/stent appli-
cations, which can further be improved by gaseous plasma treatment.

5. TiO2 NANOTUBES
In recent years, several methods have been developed to produce nano-
scale structures on titanium surfaces [47,55], such as electrochemical anodi-
zation (first used in 1984 and overlooked till 1999), template method (1996),
sol–gel process (1998), hydrothermal treatment (1999), etc. Additionally,
irregular nanomorphologies can be easily established by chemical methods.
From all of the above-mentioned methods, electrochemical anodization of
titanium is one of the most popular and well-established strategies to produce
structures with a controlled nanotopography (including nanotubes,
pillar-like nanostructures, and nanodots) on the surface of the implant.
In order to improve the biological, chemical, and mechanical properties
of biomaterials, significant research has been aimed at finding more suitable
biomaterials with nanotopography, which could offer improved bio-
performance. Over the last 2 decades, the electrochemical formation of
self-organized nanotube layers in dilute fluoride-containing electrolytes
has been studied intensively [55,57,62]. It was shown that upon anodization
of Ti in organic electrolytes with low water content, the formation of
ordered TiO2 nanoporous structures could be observed, i.e., the water con-
tent in the electrolyte is the critical factor that determines whether
self-ordered oxide nanotubes or nanopores are formed. This supports the
TiO2 Nanotubes Represent a Viable Support System 15

concept that tube formation originates from ordered porous oxide by a

“pore-wall-splitting” mechanism [63] and was also observed for higher
water content organic electrolytes for anodizations at lower voltages [64,65].

5.1 Growth of TiO2 Nanotubes

Titanium dioxide nanostructures were grown by electrochemical anodiza-
tion of titanium foils (advent, 0.1 mm thickness, 99.6% purity). First, the
foils were cleaned by successive ultrasonication in acetone, ethanol, and
deionized (DI) water for 5 min each and then dried in a nitrogen stream.
Subsequently, all anodization experiments were performed at room temper-
ature (RT) (20°C) in a two-electrode cell with the titanium foil as anode
and a platinum mesh as cathode. The working distance between the elec-
trodes was 15 mm.
All nanostructures were grown using a two-step anodization method: in
the first step a prepatterned surface is obtained and the actual nanostructures
are grown in the second step, using the prepatterned surface as substrate. The
first step was performed in ethylene glycol (EG) electrolyte (containing 1 M
H2O and 0.1 M NH4F) at 35 V for 2 h, after which the sample was ultra-
sonicated in water as to remove the grown nanotubular layer; thus resulting
in a prepatterned surface. The prepatterned surfaces were cleaned again by
successive ultrasonication in acetone and ethanol and further used as sub-
strates for the second anodization. For the second step, the electrolytes used
are EG based, having specific water and hydrofluoric acid (40% HF)
concentrations—which depend on the desired nanostructure morphology.
An overview of all the conditions used is listed in Table 1. The reason for this
two-step anodization is to obtain nanostructures with higher order and
fewer defects on the surface.
After anodization, the as-formed nanostructures were kept in ethanol for
2 h in order to remove all organic remnants from the electrolyte, followed
by washing with distilled water and drying in a nitrogen stream.

Table 1 Anodization Conditions for Different Nanotube Diameters

Anodization
NT Diameter (nm) Electrolyte Potential Used (V) Time (h)
15 nm (NT15) EG + 8 M water + 0.2 M HF 10 2.5
50 nm (NT50) EG + 8 M water + 0.2 M HF 20 2.5
100 nm (NT100) EG + 8 M water + 0.2 M HF 58 2.5
NT, nanotube.
Other documents randomly have
different content
Welcome to our website – the ideal destination for book lovers and
knowledge seekers. With a mission to inspire endlessly, we offer a
vast collection of books, ranging from classic literary works to
specialized publications, self-development books, and children's
literature. Each book is a new journey of discovery, expanding
knowledge and enriching the soul of the reade

Our website is not just a platform for buying books, but a bridge
connecting readers to the timeless values of culture and wisdom. With
an elegant, user-friendly interface and an intelligent search system,
we are committed to providing a quick and convenient shopping
experience. Additionally, our special promotions and home delivery
services ensure that you save time and fully enjoy the joy of reading.

Let us accompany you on the journey of exploring knowledge and

personal growth!

ebooknice.com