Table Of ContentRelated titles
Characterization of Biomaterials
(ISBN 978-0-12-415800-9)
Biocompatibility and Performance of Medical Devices
(ISBN 978-0-85709-070-6)
Biotribocorrosion in Biomaterials and Medical Implants
(ISBN 978-0-85709-540-4)
Woodhead Publishing Series in Biomaterials
Biofilms and Implantable
Medical Devices
Infection and Control
Edited by
Ying Deng
Wei Lv
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List of contributors
A. Bolocan Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
M.C. Chifiriuc University of Bucharest, Research Institute of the University of
Bucharest-ICUB, Bucharest, Romania
S.S. Dastgheyb Sidney Kimmel Medical College at Thomas Jefferson University,
Philadelphia, PA, United States; National Institute of Allergy and Infectious Diseases,
The National Institutes of Health, Bethesda, MD, United States
G. Dolete University Politehnica of Bucharest, Bucharest, Romania
A.R. Eberly Vanderbilt University Medical Center, Nashville, TN, United States
A.-M. Ene University Politehnica of Bucharest, Bucharest, Romania
A. Ficai University Politehnica of Bucharest, Bucharest, Romania
D. Ficai University Politehnica of Bucharest, Bucharest, Romania
K.A. Floyd Vanderbilt University Medical Center, Nashville, TN, United States
A.M. Grumezescu University Politehnica of Bucharest, Bucharest, Romania
M. Hadjifrangiskou Vanderbilt University Medical Center, Nashville, TN,
United States
S. Hahnel Regensburg University Medical Center, Regensburg, Germany
N.J. Hickok Sidney Kimmel Medical College at Thomas Jefferson University,
Philadelphia, PA, United States
A.M. Holban University Politehnica of Bucharest, Bucharest, Romania; University of
Bucharest, Bucharest, Romania
V. Lazăr University of Bucharest, Research Institute of the University of
Bucharest-ICUB, Bucharest, Romania
x List of contributors
M. Loza-Correa Centre for Innovation, Canadian Blood Services, Ottawa, Ontario,
Canada
J. Malheiro University of Porto, Porto, Portugal
B. Nicoară University Politehnica of Bucharest, Bucharest, Romania
M. Otto National Institute of Allergy and Infectious Diseases, The National Institutes
of Health, Bethesda, MD, United States
R.A. Puiu University Politehnica of Bucharest, Bucharest, Romania
S. Ramírez-Arcos Centre for Innovation, Canadian Blood Services, Ottawa, Ontario,
Canada
M. Rapa S.C.I.C.P.E. BISTRITA S.A., Bistrita, Romania
M. Simões University of Porto, Porto, Portugal
P. Stoica S.C.I.C.P.E. BISTRITA S.A., Bistrita, Romania
G.M. Vlăsceanu University Politehnica of Bucharest, Bucharest, Romania
Preface
From the late 1950s to today, implantable medical devices such as spinal implants,
reconstructive joint replacements, dental implants, cardiovascular implants, breast
implants, intraocular implants, and catheters, have extended and improved the quality
of life for millions of patients.
Rapid advances in medical devices have driven the field of implantable devices
and led to the development of many new highly potent biomaterials. The fast pace
of research and a large market demand promote the development of implant mate-
rials that focuses on optimizing and improving the mechanical and biocompatibility
properties. Recently, however, increasing attention has been paid to the implantable
device-associated infections because many implantable devices fail due to the biofilm
formation on the device’s surface and surrounding tissue. Biomaterials that promote
tissue regeneration often attract microorganism attachment. Patients with device-as-
sociated infections can suffer from morbidity, expensive device replacement surgery,
and systematic infection. Therefore, implantable device–associated infection has
become one of the most serious complications since antimicrobial treatments often
fail due to the high drug and host immune resistance of the biofilm, or bacteria develop
a resistance to the antibiotics, ultimately leading to implant failures or even mortal-
ity of patients. In addition, systemic or local administration of antibiotics may cause
severe side effects such as abdominal pain, diarrhea, rashes, ototoxicity, and renal
toxicity. These challenges, coupled with the complexity and diversity of new implant-
able medical devices, are fueling the evolution of novel biomaterials and surfaces that
overcome bacterial infections. However, despite the growing importance of antimicro-
bial biomaterials, the materials and methods are not widely available to the medical
device field.
An ideal implantable medical device should perform its therapeutic function by
being compatible with surrounding tissues, enhancing tissue regeneration, or promot-
ing bone reconstruction, while reducing the risk of infection. This direction is believed
to be one of the most promising research areas due to its large clinical requirements
and huge market potential.
Our aim in writing this book is to provide a comprehensive reference on antimi-
crobial medical devices covering basic concepts and approaches for developing new
antimicrobial biomaterials, novel approaches to reduce the risk of infection, and prac-
tical methods in product development for medical applications. More importantly,
an understanding of the fundamental concepts involved in the mechanisms of bio-
film formation, properties of biofilm, bacteria–material interactions, and the principle
of designing antimicrobial materials will help resolve the issues involved in medical
xii Preface
device–associated infection. This book may serve as an excellent introductory book or
a good source of new ideas for developing innovative antimicrobial medical devices.
Our target is to enlighten students, teachers, scientists, or people outside of the field to
see the art of bioengineering, material evaluation, and production.
Editors
Dr. Ying Deng
Dr. Wei Lv
Overview of biofilm-related 1
problems in medical devices
P. Stoica1, M.C. Chifiriuc2, M. Rapa1, V. Lazăr2
1S.C.I.C.P.E. BISTRITA S.A., Bistrita, Romania; 2University of Bucharest, Research Institute
of the University of Bucharest-ICUB, Bucharest, Romania
1.1 Introduction
Microbial adherence to a particular substrate, followed by its colonization and biofilm
formation may have a negative impact in many areas, from the industrial to the medical
one. Therefore, understanding the mechanisms of adhesion and formation of microbial
biofilms is essential for the establishment of effective measures to prevent and combat
them (Kaali et al., 2011). Microbial biofilms may be formed at any liquid–solid (e.g.,
the surface of prosthetic medical devices (MDs), the surface of the stones in the aquatic
environment, the ships’ submerged surface), liquid–liquid (oil-water tanks oil), liquid–
air (e.g., plant leaves, roots) interfaces, or on the surface of the epithelial and animal
tissues (e.g., teeth, digestive and respiratory tract) (Hamilton, 1987; Lazăr, 2003). The
discovery of microbial biofilms is attributed to Antonie van Leeuwenhoek who, in the
18th century, was the first researcher who examined the so-called “animalcules” in the
dental plaque collected from his own teeth, but Costerton et al. (1978), have postulated
the general theory of the biofilm formation based on data from the study of microbial
biofilms formed in the natural aquatic ecosystems (Lazăr, 2003; Sousa et al., 2011).
The biofilm is defined as a community of microbial cells attached irreversibly to the
substrate at the interface or to each other, embedded in an exopolysaccharidic (EPS)
matrix produced by the biofilm cells, which show phenotypic changes (Lazăr, 2003).
In nature, microorganisms coexist in 99% under the form of biofilms, which suggests
resistance and/or a selective advantages for sessile cells compared to their planktonic
counterparts. So sessile cells are physiologically different from those who live freely.
The main changes in phenotype are linked to gene transcription, growth rate, intensity
of the respiration processes and electron transport, synthesis of extracellular polymers,
rate of substrate degradation, and the ability to survive in the presence of microbicidal
factors (Flemming, 1998; Sousa et al., 2011; Costerton et al., 1987; Hall-Stoodley
et al., 2004; Dufrȇne, 2008; Donlan and Costerton, 2002; Wilson, 2001). The bio-
films can contain bacteria, fungi, protozoa, algae, and their associations, usually the
constitutive cells requiring similar conditions to initiate the progress of cell growth.
The factors that influence the formation of biofilm are very diverse, such as humidity,
temperature, pH value of the environment, weather conditions, and the chemical com-
position of the nutritive substratum. In addition to microorganisms, biofilms contain
80–90% water. Biofilm thickness can vary between 50 and 100 μm, depending on the
colonized area (Kaali et al., 2011).
Biofilms and Implantable Medical Devices. http://dx.doi.org/10.1016/B978-0-08-100382-4.00001-0
Copyright © 2017 Elsevier Ltd. All rights reserved.
4 Biofilms and Implantable Medical Devices
1.2 Development of microbial biofilms on biomaterials
used in medicine
The adherence of pathogens on the surface of susceptible cells/inert supports is medi-
ated by microbial structures called adhesins, with a great structural and biochemical
diversity (Lazăr, 2003). MDs are used in almost all diagnostic and therapeutic medical
procedures, and depending on their specific application, they are composed of differ-
ent materials such as, polymeric, metallic, or ceramic ones (Frederick, 1994). The
MD that are used in the internal medium or are partially in contact with the tissues of
the human body must meet a series of criteria, such as biocompatibility, strength, and
stability, in relation with tissues, enzymes, cells, and various body fluids (Kaali et al.,
2011). If the host-body tissues do not perfectly adhere to the biomaterial surface, there
occur conditions that are favorable for microbial adherence, and hence for the forma-
tion of microbial biofilms. Therefore, one could state that biocompatibility is inversely
related with the microbial adherence capacity (Lazăr, 2003). In the past 20 years it
was found that 6–14% of the hospitalized patients develop nosocomial infections that
are in general associated with internal or partial internal MDs (invasive MDs), such
as tracheal prostheses, pacemakers, endotracheal tubes, urinary catheters, peritoneal
dialysis catheters, contact lenses, dental implants, orthopedic implants, surgical soft
tissue prostheses, and so on (Sousa et al., 2011).
1.2.1 Interaction of microbial strains with biomaterial surface
Emphasizing the significance of ecological, health, and economic phenomenon of
microbial adhesion and aggregation prompted the escalation of research in this area.
Microbial adhesion to different natural (skin, mucosa) and artificial (catheters and
implants) substrates is a prerequisite of the pathogenicity of microbial infections.
Microbial adherence phenomenon has been studied most in terms of colonization of
solid–liquid interface.
Microorganisms, like most of their potential colonization substrates, whether
organic or inorganic, have a negative charge on their surface and different degrees of
hydrophobicity (Lazăr, 2003). Based on these physicochemical properties of microor-
ganisms, van Loosdrecht et al., 1990, cited by Zarnea, 1994 and Busscher et al. (1995)
argue that bacterial adherence and biofilm formation develop in four stages: (1) trans-
port (movement of microorganisms in the environment toward the substrate surface)
by: (a) diffusion, which is the result of Brownian motion, in static environments; (b)
convection displacement currents associated with fluid movement, ensuring a faster
transport; (c) active movement, which is the fastest in case of a concentration gra-
dient for certain substances between the two interfaces; (2) initial bonding that is
reversible, with the possibility of removal of the bacteria attached either by their own
mobility, or by gentle agitation; (3) permanent irreversible binding with the possi-
bility of removal of bacteria adhering only under the action of strong shaking forces
(Table 1.1); (4) colonization, in which the cells irreversibly bound to the substrate
and between them begin to grow and quickly multiply, resulting in microcolonies and
subsequently in mature biofilms (Lazăr, 2003).
Overview of biofilm-related problems in medical devices 5
Table 1.1 Chemical interactions occurring in the stage of
stabilization of adhesion depending on the distance between
the two contact surfaces (Laz r, 2003)
ă
Distance bacterial
Interaction cell–substrate
Van der Waals >50 nm
Van der Waals and Coulombian 10–20 nm
Van der Waals, Coulombian, and others 1–5 nm
After colonization, biofilm growth becomes multilayered and can be colonized by
other species incapable to start the colonization process alone, resulting in a complex
biofilm. When the biofilm becomes thick due to the large amount of specific poly-
mers accumulation, the deeper layers of the biofilm become anoxic; this phenomenon
induces starvation and biofilm destabilization, causing the detachment of biofilm from
the solid surfaces. The detached biofilms can colonize new surfaces, repeating the
cycle (Lazăr, 2003).
Microorganisms reach the surface of MD through several mechanisms: (1) direct
contamination, (2) adjacent paths, and (3) blood. Microorganism–biomaterial adhesion
is due to van der Waals forces and hydrophobic interactions. In general, the microbial
cells are charged negatively similar to biomaterials surface and therefore, they will be
rejected, but van der Waals forces overcome the repulsive forces, the microorganisms
being held at about 10 nm away from the surface of the MDs, rendering possible their
initial attachment. Several microorganisms as well as MD could have a hydropho-
bic surface, cases in which hydrophobic forces play an important role in microbial
attachment. It was demonstrated that hydrophobic forces are 10–100 times stronger
than van der Waals forces at a distance of 10 nm from the biomaterial surface. Hydro-
phobic forces and electrostatic repulsion will easily allow the irreversible adherence
of microorganisms on the surface of the MD. The specific mechanisms involved in
the irreversible adhesion were studied for Staphylococcus aureus and Staphylococcus
epidermidis biofilms, as they are two of the most common bacteria encountered in
prosthetic/implantable MD-associated infections (Lazăr and Chifiriuc, 2010).
The main MDs that may be compromised by the formation of biofilm-associated
infections are: intravascular implants (central venous catheters—Cook, Arrow, Hickman,
Broviac, Groshong, arterial and venous peripheral catheters, pulmonary arterio-venous
catheters); cardiovascular implants (heart valves, ventricular assist devices, coronary
stents, vascular grafts, pacemakers); neurosurgical implants (ventricular shunts, neurolog-
ical stimulators, Ommaya reservoirs, intracranial pressure measuring devices); orthopedic
implants (prostheses joints, fasteners, spinal implants, hip replacements, orthopedic recon-
structive implants); ophthalmic implants (lenses, glaucoma tubes) and dental implants;
gynecological implants (breast implants) (von Eiff et al., 2005); and urinary catheters and
intravenous (Kaali et al., 2011), respiratory assistance devices (endotracheal tubes, cannu-
las for tracheostomy) (Guggenbichler et al., 2011).
