Solution y

EXECUTIVE SUMMARY
The application of medical devices either for temporary or permanent us

e has become an indispensible part of almost all fields of medicine. How
ever, foreign bodies are associated with a substantial risk of bacterial and
fungal infections. Implant-associated infections significantly contribute t
o the still increasing problem of nosocomial infections. To reduce the inc
idence of such infections, specific guidelines providing evidence-based r
ecommendations and comprising both technological and nontechnologic
al strategies for prevention have been established. Strict adherence to hy
gienic rules during insertion or implantation of the device are aspects of
particular importance. Besides such basic and indispensable aspects, the
development of new materials which could withstand microbial adheren
ce and colonization has become a major topic in recent years. Modificati
on of surface by primarily physico-chemical methods may lead to a chan
ge in specific and unspecific interactions with microorganisms and, thus,
to a reduction in microbial adherence. Medical devices made out of a ma
terial that would be ideally antiadhesive or at least colonization-resistant
would be the most suitable candidates to avoid colonization and subsequ
ent infection. However, it appears impossible to create a surface with an
absolute zero-adherence due to thermodynamical reasons and due to t
he fact that a modified material surface is in vivo rapidly covered by plas
ma and connective tissue proteins. Therefore, another concept for the pre
vention of implant-associated infections involves the impregnation of de
vices with various antimicrobial substances such as antibiotics, antiseptic
s, and/or metals. In fact, already commercially available materials for cli
nical use such as antimicrobial catheters have been introduced, in part wi
th considerable impact on subsequent infections. However, future studies
are warranted to translate the knowledge on the pathogenesis of deviceassociated infections into applicable prevention strategies.
Table of Contents
Topic
Pag
e Nu
mbe
r
Introduction.
Materials for Biomedical Applications.
Modalities for Analysis
Atomic Force Microscope.
Spectroscopic methods..
12
X-ray photoelectron spectroscopy..
14
Attenuated total reflection Fourier transform infrared spectr

oscopy (ATR-FTIR).
21
Pathogenesis.
22
Attachment of Microbe on Device Surface
23
Management of Medical Device Associated Infections :

General Considerations
Removal of Device.
28
Salvage of Device and Treatment with Antimicrobial Agents

.
Prevention by Material Modification..
Development of Antiadhesive Polymer Materials by Physico-
30
Chemical Modification,.
31
Conclusion..
References..
32
36
42
43
Introduction
The rate of implant surgery is steadily increasing. Each implantation is a

ssociated with a risk of infection. The interface between implant and tiss
ue is known to be an extremely sensitive region. Infections can arise fro
m bacteria adhering to the implant and subsequent biofilm formation and
also from tissue damage caused by instability of the implant, which can r
esult in depletion of the immune defenses [1]. Device associated infectio
ns present therefore one of the most important risk factors with respect
to revision surgery [1,3]. Since biofilms are challenging to treat with con
ventional antibiotics [4,5], avoiding the initial bacteria attachment on the
implant surface is considered as the most effective method to minimize a
nd prevent infections as well as to improve the interfacial stability.
Functionalizing biomedical implants by surface modifications for tailore
d tissue response is a growing field in research. Localized antimicrobial
delivery methods have been explored as attempts for time effective treat
ment to prevent the origin of biofilm formation [6]. For the design of im
plant materials with therapeutic coatings for local drug administration, th
e coating needs to comply with certain requirements, such as bioactivity,
mechanical stability, good substrate adhesion and the ability to carry dr
ugs. These functionali- ties can contribute towards achieving a better fix
ation to the bone as well as the release of drugs to treat infections close t
o the implant. Hence, functional implant coatings can be seen as a potent
ially promising step to achieve longer life spans for implanted devices an
d long-term surgical success rates and thereby contribute towards reduci
ng health care costs.
Materials for Biomedical Applications
Biomaterials, utilized to reinstate a broken construction and purpose in t

he human body, have revolutionized the rehabilitation of patients alongsi
de harsh functional impairments. Whereas the bulk properties of the im
plant physical are recognized to impact the presentation of the implant in
vivo, the biological host reply is more affected by external properties suc
h as chemical constitution, crystallinity, roughness and external price [7].
The clinical accomplishment for implants that are utilized in bone-interfa
cing requests is described by the extent of link of presently industrialized
bone alongside the implant external [8]. The integration of the external, s
ynthetic physical across contact alongside the living tissue is denoted to
as bioactivity. Bioactive materials, such as bio- glass [9], ceramic apatite
-wollastonite [10] as well as titanium (Ti) metals and alloys have been pr
oven to advance bone formation and to form a stable link to bone [11]. I
n finish, bioactive materials could spontaneously form a bone-like apatit
e layer on their surfaces on link alongside body fluids [12,13]. A materia
ls bioactivity can be discovered both in vivo and in vitro [14]. The mate
rials utilized as substrate and/or coatings in this thesis are described in t
he pursuing sections.
Surgical implants made of Ti or Ti alloys are extensively utilized in bio
medical requests [15]. Examples of their use are as dental implants, hip j
oints, manmade knee joints, bone plates, screws for fixation and valve pr
ostheses. The expansive scope of clinical requests is established on the m
echanical strength, biocompatibility, non-toxicity, machinability and thei
r skill to osseointe- grate [15,16].
Calcium phosphate ceramics are usually utilized in assorted fields of biohealth applications. HA, alongside the chemical formula Ca10(PO4)6(O
H)2, is the most usually utilized bioactive ceramic physical in clinical ap

plications. Its use is established on its brilliant affinity to bone [17]. This
property is due to the fact that HA is a main constituent of bones and teet
h. The bioactive property of in vitro produced HA is evidenced by the sp
ontaneous formation of a biologically produced HA layer on the external
after implanted into bone [18].
MODALITIES FOR ANALYSIS
Surface properties have an large result on the accomplishment or wreck
of a biomaterial mechanism, therefore signifying the substantial significa
nce of and the demand for adequate characterization of the biomaterial s
urface. Microscopy methods utilized in the scutiny of biomaterial surface
s contain scanning electron microscopy, transmission electron microscop
y, atomic power microscopy, and confocal microscopy. Spectroscopic m
ethods contain Scan photoelectron spectroscopy, Fourier Change infrare
d attenuated finished reflection and secondary ion mass spectrometry. Th
e measurement of link slants, even though one of the preceding methods
industrialized stays a extremely functional instrument in the evaluation o
f external hydrophobicity / hydrophilicity. Choice of the external charact
erization method utilized can be affected by a plethora of thought s enco
mpassing the kind of measurement needed, the extent of the analyzed ext
ernal span, the needed precision and accuracy, the impact of the method
on the external (i.e. does the probe, electron beam, ion beam, X-ray, nee
ded example arranging , or the scutiny nature instigate unwanted results
on the external of interest) , the impact of the example on the instrument
, limitations imposed by the external, as well as the ease of use and poten
tial y of supplies [19, 20]. In supplement , a extremely realistic factor or
constrain t that could impact the choice of external scutiny s method s uti
lized is that countless external scutiny s abilities have come to be centrali
zed, and there are momentous prices associate d alongside example proc
essing g and arranging , the timed custom of supplies, and technician tim
e.
Atomic power microscopy. Atomic power microscopy (AFM) has come
to be the most public kind of scanning microscopy utilized for polymeric
biomaterial s [25]. A three-dimensional picture of the external is crafted
by scanning a tip attached to the conclude of a cantilever across the exter
nal and monitoring g the minute powers of contact amid the example ext
ernal and probe [12, 25]. The powers of contact could be repulsive or ap
pealing and this gives development to the disparate modes of procedure
of the AFM. A extremely elevated resolution of external topography can
be obtained, with dimensions on the nanometer scale [12, 13], even thou
gh it ought to be noted that properties and dimension s of the cantilever a
nd tip, as well as the selected mode of procedure , frolic an vital act in as
certaining g the sensitivity and resolution of the acquired image. Unlike
electron microscopes , a momentous supremacy of AFM is that example
topographies , as well as surfaces roughness benefits , can be obtained la
cking external treatment or coating that could damage or change the phy
sical external below investigation n [12, 13, 16, 26, 27]. Furthermore, A
FM pictures can be acquired below vacuum, air, or fluid conditions. The
skill to picture polymeric materials inside an aqueous nature is tremendo
usly functional in the biomaterials earth, as it permits for the examinatio
n of the external of biomaterials in an nature t comparable to one that sho
uld be discovered in an implant situation, therefore permitting for the exa
mination of vibrant procedures such as erosion, hydration, and adsorptio
n n at interfaces. For example, it is probable to visualize e individual l pl
asma protein molecule s below aqueous nature s employing period imagi
ng AFM [12, 13, 28]. Even though AFM is clarifying to be an tremendou
sly functional method e in bestowing g a 3D visualization n of the bioma
terial l surfaces being learned, the period needed, reliant on such factors
as scan size and scan rate, to attain quality pictures can be momentous (i
.e. in excess of 20 min / image). In supplement, as normally y scan sizes
are tiny (i.e. fluctuating from 500 nm-500 nm to 15 m-15 m), variation
s in the external could be missed.
AFM link mode. In link mode, the AFM tip scans across a external at
extremely low power and is noticed by repulsive powers replacing amid
the tip and the external atoms. A photodiode detector monitor s the detec
tions of a laser light imitated from the tip of a cantilever. A feedback loo
p uphold s steady t detection of the cantilever, by vertically advancing th
e scanner as it scans laterally across the surface. A computer stores the
data n and a topographic c picture alongside potentially y atomic-scale e
resolution is generated. The powers at the tip are extremely tiny (0.01 to
1.0 N / m in air) and metal or hard polymeric surfaces are not usually bro
ken [7]. Though, the lateral clip powers provoked by the scanning gestur
e could change soft materials, therefore distorting g measurement data an
d provoking damage to the example [29]. Obtaining pictures of hydrated
polymeric materials in fluid could be more hindered by the fact that a litt
le hydrate d polymers are softer than dried examples managing to an rise
in example deformation and damage and a decreased picture quality eme
rging g from the dragging gesture of the tip.
AFM non link mode. In non-contact mode, appealing rather than repu
lsive powers are measured. The scanning tip is oscillated perpendicular t
o, and just above the example external alongside an amplitude normally l
ess than 10 nm. As alongside link mode, a photodiode detector monitor s
the deflections of the laser light imitated from the tip of a cantilever. A f
eedback loop maintains steady oscillation amplitude or frequency, as the
scanner moves laterally. A computer stores the data and a topographic pi
cture, alongside a lower resolution than in link mode, is generated. Nonlink mode could work well alongside hydrophobi c polymers. Though hy
drophilic polymers or imaging in a fluid nature t in non-contact mode is

not normally utilized due to the low resolution obtained.
AFM tapping g mode. In tapping mode, the cantilever r is vibrate d at
or adjacent its resonance e frequency, and lightly taps the example extern
al alongside an amplitude e normally fluctuating from 20 to 100 nm. A te
ar photodiode e detector monitor s the deflections of the laser light imitat
ed from the tip of the cantilever r. A feedback loop maintains steady t os
cillation n amplitude e or frequency, as the scanner moves laterally acros
s the surface. This mode consequently uphold s the high-resolution skills
s of link mode but is not annihilative e as there are no lateral frictional l
powers requested to the example that can distort t or damage the physical
[12]. Tapping mode AFM has proved to be extremely prosperous l for hi
gh-resolution studies s of polymeric c biomaterials permitting for charact
erization n of nanometer scale features not visible e by supplementary mi
croscopic method s (see Fig. 3). Tapping mode AFM pictures normally y
contain d in the biomaterial l works e have a scan size fluctuating from
500 nm to 500 nm, to 15 m to 15 m.
AFM period imaging mode. The period imaging mode can be utilized
to chart the external constitution n of a sample. In this mode, the cantilev
er r is vibrate d at or adjacent its resonance e frequency, and lightly y tap
s the example surface. A feedback loop maintains steady t oscillation n a
mplitude, as the scanner moves laterally y across the surface. A period pi
cture displays the period difference amid oscillations of the piezoelectric.
Crystal that propels the cantilever r and oscillation n of the cantilever r it
self as it interacts alongside the surface. Period imaging can expose fine
features that are obscure d by a rough external topography y. Though fac
tors such as external hardness, elasticity y, adhesive properties, and exter
nal price could alter the period pictures obtained. Period and tapping g m
ode (height) pictures can be obtained d simultaneously y (see Fig. 4), so t
he locale n of the external features discern d in a period picture can be co
rrelated undeviatingly alongside the external topography y. This mode ca
n consequently be utilized to ascertain the size, form and spacing of disp
arate physical areas that might not or else be discerned d from height alo
ne [27, 30]. For example, period imaging AFM can prosperously y notic
e adsorbed d protein s that are not observable e in standard l topographic
c pictures, as proteins imaged on surfaces alongside roughness s adjacent
the dimension s of the protein cannot be discriminated d from the physic
al topography y alongside standard l AFM [27], that is manipulated to im
aging protein s merely on smooth
surfaces (1 m2 roughness s of <0.5 nm) [30, 34].
AFM employing coated tips. Currently the manipulation of AFM has bee
n couple d alongside appropriate e biomolecule s to enable the discover o
f contact s of the external alongside assorted s protein s and lipids. As thi
s method has been requested extra frequently to discover specific contact
s alongside biological l arrangements encompassing g polysaccharide s o
f living g microbial cells [31], as well as extracellular r ATP on living g
cells [32], it has additionally been requested to the characterization n of
polymeric [33, 34] and metallic [35] materials. The use of these method
s has added an supplementary l dimension n to AFM in supplement n to t
hat utilized conventionally y for scutiny of morphology y and topograph
y y of a biomaterial l surface.
Often a collection of characterization n method s are utilized in the evalu
ation n of biomaterial l surfaces. Though, it ought to be noted that the us
e of even disparate microscopic c method s could give development to a
disparate think of the surfaces obtained. Figures 1, 2, and 3 display SEM,
TEM and AFM pictures suitably y of the alike polyamide e polymeric c

material. The aftermath obtained d by SEM display a fairly flat external,
alongside a little extremely different t porous regions. TEM aftermath di
splay a flat external, and in supplement n display that the bulk polymer e
ncompasses a deep prop t layer encompassing g of interconnected d exce
edingly y porous domains. AFM aftermath display momentous external
morphology y, not visible e by the supplementary method s used. Thus, t
he combination n of microscopic methods utilized could frolic a priceles
s act in the characterization n of external features and morphology y of p
olymer biomaterials.
Spectroscopic methods
Spectroscopic methods are extensively utilized to expose priceless data c
onsidering the constituent agents and chemical construction adjacent the
external span of a example [46]. Two new characterization methods utili
zed in the biomaterials earth are scanning transmission Scan microscopy
(STXM), and photoelectron emission microscopy (PEEM). Both metho
ds need synchrotron light origins and elevated instrumentation. As STX
M has the gains of not being altered by example charging or topography,
as well as the skill to picture the example in resolution, the depth of sam
pling is maximum lm frequently on the order of 100 nm. PEEM has a sa
mpling depth of normally y 510 nm for polymers. Both methods, STX
M and PEEM, have a elevated lateral spatial resolution on the order of
50 nm, and brilliant chemical sensitivity y. One more paper in this distin
ct subject will debate the relevance of these two growing methods (STX
M, PEEM) in the biomaterials field. Far extra usually utilized in the exte
rnal characterization of biomaterials, the established spectroscopic metho
ds utilized include:
Auger electron spectroscopy (AES).
X-ray photon spectroscopy (XPS).
Secondary ion mass spectrometry (SIMS).
Attenuated total reflection Fourier transform infrared spectroscop

y (ATR-FTIR).
Auger electron spectroscopy (AES). Auger electron spectrosco

py (AES) has been utilized for investigating external morphology
[47], and in particular elemental analysis. A concentrated beam o
f electrons is utilized to stimulate Auger electrons from the extern
al, that are next noticed and analyzed. No distinct example arrang
ing is needed and data collection is quick (i.e. a insufficient minu
tes) and reproducible. This method has proven extremely functio
nal in a little engineering fields for elemental scutiny and constitu
tion depth profiling. Though, in finished AES is manipulated in it
s use in the scutiny of polymeric biomaterials as it is usually belie
ved improper for studying organic matter. Organic examples fact
ually burn up in the electron beam, radically changing the chemis
try and morphology of the example being measured [20]. Becaus
e the chance of artefact and misinterpretation is colossal, the use
of AES for describing organic, polymeric or biological specimen
s have to be approached alongside alert [20].
X-ray photoelectron spectroscopy. Scan photoelectron spectros

copy (XPS),
AKA ESCA (electron spectroscopy for chemical analysis) is exte
nsively utilized in biomaterial requests to ascertain the elemental
constitution of solid surfaces [48]. Distinct example arranging is
usually not needed for XPS, even though external contamination
on storage or across transport from the scutiny laboratory to the
XPS abilities could precisely have an adverse result on the XPS a

ftermath obtained. In supplement, additives, such as catalysts that
could be utilized across the polymerization of polymeric biomate
rials, or impurities can be present at the external of the polymers
and therefore give considerably to the XPS aftermath obtained.
The principle e of XPS is established on the emission of electrons
from matter
in reply to irradiation of the external by a beam of monochromati
c X-rays.
The kinetic power of the emitted photoelectrons (KE ) is exceptional for
the disparate agents as well as being sensitive to the chemical state of the
atoms [8, 48].
Figure 5a. Survey (low resolution) XPS scans of a polyurethane (PU) su

rface, and a PU surface
modified with polyethylene oxide (PEO). XPS signals for carbon
(C), nitrogen (N) and oxygen (O) are indicated. Scans show an in
crease in the O peak. Table 1 shows the corresponding atomic
%of oxygen present clearly indicating that the surface has been s
uccessfully modified with PEO. XPS spectra were obtained using
a Leybold MAX200 X-ray photoelectron spectrometer, and analy
zed using ESCATOOLS (Surface/ Interface, Mountain View, CA
). Figure courtesy of J. Tan and J. L. Brash.
because typicall y extra period is consumed buying data above a
narrower power scope as contrasted to a survey scan (Fig. 5a) em
erging in a larger gesture to sound ratio. The XPS method is exce
edingly flexible, alongside a sampling depth connected to the inel
astic mean free trail of photoelectrons in the external span, that is
normally larger that 30 for polymeric materials, even though th
is depends on both the photoelectron power and on the physical l
earned [49]. Typically, the gesture, below ultra-high vacuum, is g
athered from a colossal example span (i.e. 6 mm in diameter)
Figure 5b. High resolution XPS C1s detailed spectra of a polyur

ethane (PU) surface, and a PU surface modified with polyethylen
e oxide (PEO). Representative 4 peak curve fits of the XPS C1s s
ignal are also shown. Table 2 shows the corresponding Carbon A
tom Bonding (%) of C O C determined from best t of C1s High
Resolution XPS Spectra clearly indicating that the surface has be

en successfully modified with PEO. XPS spectrum was obtained
using a Leybold MAX200 X-ray photoelectron spectrometer, and
analyzed using ESCATOOLS (Surface/ Interface, Mountain Vie
w, CA). Figure courtesy of J. Tan and J. L. Brash.
in order to minimize collection period, and probable damage to a

little polymeric materials. Though, lateral resolution employing a
tinier example span, in the scope of square microns, has been des
cribed [48]. Refined instrumentation simplifies sampling graspin
g and data collection [8]. Well industrialized theory and compute
r plans are obtainable to assist in the clarification of the data obtai
ned. XPS is believed to be a moderately non-destructive method,
even though a little care is demanded to safeguard that the Scan
does not change the external chemistry [20]. Setbacks have been
described to transpire alongside polymers, exceptionally flouropo
lymers, alongside the results being minimized by use of a monoc
hromatic basis in conjunction alongside an competent compensati
on method to circumvent external charging setbacks or by plainly
minimizing the Scan exposure to the external and optimizing spe
ctral buy periods [11]. Data concerning useful clusters can be obt
ained by employing derivitization replies [8, 50]. Compositional
variation as a purpose of example depth can be obtained by meas

urement of the photoelectron intensities at disparate emission sla
nts, termed slant resolved XPS [8, 51]. Slant resolved XPS can a
dditionally be utilized to scrutinize an overlayer that could not be
uniform, to examine a external whereas coverage is trusted to be
patchy [11], or to scrutinize the change or transition amid bulk an
d external of a surface modified material. To attain elemental
data countless thousand angstroms into the example, argon etchin
g can be utilized in conjunction alongside XPS even though this
method is example annihilative [8]. As the gesture is normally ga
thered from a colossal example span (i.e. 25 mm2), it is probable,
as remarked preceding, to use XPS to ascertain lateral variations i
n external constitution [8] and to guesstimate the thickness of bot
h organic and inorganic c layers [52]. In supplement, hydrated fre
eze dried surfaces can be examined employing XPS [8] that coul
d be of substantial attention after describing polymer surfaces tha
t could reorient on exposure to an air, vacuum or aqueous nature .
There is substantial works obtainable on the principles of XPS, a
nalytical procedures, instrumentation and ways to quantitative an
alyses [3, 8, 49, 5355]. In the discover and characterization of bi
omaterial surfaces, XPS is perhaps y the most extensively utilize
d technique. It has been utilized for a collection of surfaces and e
xternal modifications, encompassing studies of adsorption and ret
ention of chemicals such as antibiotics and bonding agents [11], f
or the detection of immobilized proteins [20], understanding the c
hemistry of the construction, formation and stability y
of plasma indulged surfaces, [7, 52, 5659] as well as for the cha
racterization of the steps of formation of slender coatings [60].
Secondary ion mass spectrometry (SIMS) and time-of-flight s

econdary ion mass
spectrometry (ToF-SIMS). Secondary ion mass spectrometry (S
IMS) is competent for bestowing methodical molecular external
data [7] and increased custom of this method in the external char
acterization of polymeric biomaterials has been noted in present
years. Typically, no distinct example arranging is needed for SIM
S. Though as alongside XPS, the external have to be clean and fr
ee of each contamination that could transpire on storage or transp
ort. Surfaces are assaulted alongside a concentrated beam of ions
or atoms and the power from the event beam (approximately 5
25 keV) is transferred to the external zone of the physical emergi
ng in the emission of secondary particles, a little of that are ioniz
ed, at and concerning the encounter locale [8]. These ionized part
icles are separated as a purpose of the ration of mass each mecha
nical price and affirmatively and negatively charged species are n
oticed in two disparate buys [61]. Low flux or static SIMS afterm
ath in negligible damage to the example and the fragments emitte
d are characteristic of the external molecular construction [8, 62].
Elevated flux, or vibrant SIMS aftermath in quick etching of the
external across scutiny and can be utilized to monitor adjustment
s in the elemental constitution alongside depth [8, 61]. Time-of-fl
ight SIMS (ToF-SIMS) is a extremely effectual method for descri
bing the elemental (including H and isotopes) and molecular cons
titution of the top external of biomaterials [61]. Events in the ToF
-SIMS analyzer have increased the skills of static SIMS due to co
nsiderably enhanced mass transmission (independent of the ion m
ass), mass resolution, mass scope and sensitivity [61]. In this case
, the example external is assaulted alongside extremely short-puls
ed ion beams. Amid two consecutive pulses, all of the secondary

ions are removed and electrostatically accelerated into a earth fre
e drift region. Lighter ions will have higher velocities and hence
will grasp the detector at the conclude of the drift span preceding
than the heavier crowd [61]. From the period of flight, the mass t
o price ratio can be ambitious [61]. Below static conditions, there
is negligible external damage alongside ToF SIMS [61]. SIMS ca
n be utilized for the identification of all agents encompassing hy
drogen [8] as well as atomic and molecular ions [61] and tremen
dously elevated mass fragments at extremely low concentrations.
Even though the scutiny destroys the external, data generated is u
ndeviatingly connected to the early external [20]. As static SIMS
can be requested prosperously to the scutiny of both organic and i
norganic surfaces, the accuracy of the data alongside vibrant SIM
S is considerably decreased for organic and biological surfaces
[20]. These methods can be utilized to attain manage facts of cov
alent attaching of molecules to a external [66], as well as to forec
ast supplementary external properties encompassing wettability,
adhesiveness, and biological reactivity [61]. SIMS spectra can fur
nish characteristic fingerprints for biomaterial surfaces [67], an
d has been utilized to associate external chemistry alongside cell
development [56] as well as for monitoring the degradation kineti
cs of biodegradable polymers employing molecular heaviness all
ocations of the oligomeric hydrolytic c reply produce [6870]. Te
mperature-programmed SIMS proposals data on adsorption powe
r and therefore helps to discriminate h amid physisorption and ch
emisorption phenomena [71]. It is frequently utilized in conjuncti
on alongside XPS to scrutinize the integrity y, mean thickness an
d chemical state of multi-layer biomaterial coatings [72], corrobo
rating link slant and XPS measurements and complementing data

obtained from less external sensitive methods [61].
Infrared spectroscopy (IR) and attenuated finished reflection

Fourier change infrared spectroscopy (ATR-FTIR). Infrared s
pectroscopy is utilized to attain data concerning molecular constr
uction by computing the frequency of IR radiation demanded to s
timulate vibrations in molecular promises [24]. Example arrangin
g is negligible including request of the polymeric physical of atte
ntion, in film form, onto a crystal element. Instrumentation is mo
derately inexpensive, and the emerging spectra furnish chemical
bonding data [7]. Infrared spectroscopy in attenuated finished refl
ection (ATR-FTIR) couples the analytical method of infrared spe
ctroscopy alongside the physical phenomena of finished inner ref
lection (i.e. reflection and refraction of electromagnetic radiation
at an interface of two mass media possessing disparate indices of
refraction) to restrict the analyzed volume on the external span of
the example [73, 74]. For this method, the event electromagnetic
waves are completely imitated back into the early medium. The e
lectromagnetic earth is instituted in the subsequent medium as e
mbodied by an transient wave due to diffraction at the borders of
the event radiation at the interface [73]. In attenuated finished ref
lectance (ATR) sampling mode the subsequent medium is the ph
ysical to be learned, alongside the early medium replacing as the
inner reflection agent [24, 73]. Data concerning the molecular co
nstruction of the physical, inter- and intra-molecular contact, crys
tallinity, conformation (e.g. proteins) and orientation of molecule
s can be obtained across scutiny of the infrared spectra [74, 75].
Even though depth profiles can be obtained employing this meth
od, the XPS and SIMS methods debated preceding are believed f
ar extra external sensitive.
Pathogenesis
The skill to adhere to materials and advance formation of a biofil
m is an vital feature of the pathogenicity of bacteria encompassed
in external body infections. The fact that staphylococci embody t
he main organisms associated alongside infections of health mec
hanisms has considerably spurred scutiny on pathogenic mechani
sms, emerging in vital advances in our understanding of biofilm
formation. Thus, a battery of staphylococcal virulence factors hav
e been recognized and described in the past two decades managin
g to vital visions, partic- ularly alongside respect to the contact of
the bacteria alongside the external of the implanted or inserted de
vice. Normally, CoNS live in balanced harmony on our skin, gro
wing the main constituent of the cutaneous microflora. Beyond th
e setting of a health mechanism, these organisms scarcely cause i
nfections. Though, in relation to an inserted or implanted externa
l body, these bacteria are able to colonise the external of a
foreign body by the formation of a deep, multilayered biofilm.
[25,26] Biofilm formation proceeds in two stages: a quick attach
ment of the bacteria to the external of the implanted mechanism i
s pursued by a extra spread accumulation period that involves ce
ll proliferation and intercellular adhesion (figure 1). For years, ef
fortifications have been made to recognize bacterial factors acco
untable for every single of both phases.
Attachment of Microbe on Mechanism Surface
Microbial adherence to external bodies depends on the cell extern

al characteristics of the micro- organisms and on the nature of the
external body material. Factors encompassed contain physicoche
mical
forces such as polarity, London-van der Waals powers and hydr
ophobic interactions. [27] Cell external hydrophobicity and early
adherence of S. epidermidis to polystyrene have been attributed t
o two disparate bacterial surface-associated proteins, labeled SSP
-1 and SSP-2. [28] Early attachment of S. epidermidis to a poly
mer external could be additionally mediated at least in portion b
y AtlE, a surface-associated autolysin. [29] The biofilm-associa
ted protein Bap was described to give to both periods of S. aureu
s biofilm formation, adhesion and accumulation, [30] as Bhp, a
Bap-homologous protein, could give to S. epidermidis biofilm for
mation. [31] Aside from proteins, a polysaccharide struc ture sho
uted capsular polysaccharide/adhesin (PS/A) has been associated
alongside early adherence and slime production. [32] In a rabbit
ideal of endocarditis, PS/ A-deficient mutants were less virulent
and im
munisation alongside PS/A arose in protection opposing infectio
n. [33] As the manage contact amid bacteria on one side and the
unmodified and naked external of the external body on the suppl
ementary side plays a critical act in the main periods of the adher
ence procedure in vitro and plausibly additionally in vivo, supple
mentary factors could be vital in afterward periods of adherence
in vivo. Implanted mechanisms quickly come to be coated along
side plasma and connective tissue proteins, such as fibronectin, fi
brinogen, vitronectin, thrombos- pondin, laminin, collagen and v
on Willebrand factor (vWf), that afterward could assist as specifi
c receptors for colonising micro-organisms. [34-36] In the vascu

lar arrangement at locations of increased flow, vWf could additi
onally frolic an vital act in adhesion of staphylococcal cells to pol
ymer surfaces because below elevated clip rates platelets do not a
ppreciably attach to extracellular matrix proteins supplementary t
han vWF. [35] Countless host factor-binding proteins from S. a
ureus (e.g. the fibrinogen receptor ClfA and the fibronectin-bindi
ng proteins FbpA and FbpB) and from CoNS (e.g. the fibrinogenbinding protein Fbe and the fibronectin-binding autolysin Aas) ha
ve been recognized and characterised.
The S. epidermidis autolysin AtlE that mediates main attachment

to a polymer external (see serving 2) was additionally discovered
to display vitronectin-binding ac tivity, counseling not merely a p
urpose in the main periods of adherence but additionally a contrib
ution to afterward periods of adherence including specific contac
t alongside plasma proteins deposited on the polymer surface.
[29] Aside from proteins, teichoic acid was sug gested to purpos
e as a bridging molecule amid the bacteria and fibronectin-coate
d polymer. [37]
Cell Proliferation & Intercellular adhesion

Once adhered to the external of the external body, micro-organis
ms increase and amass in multilayered cell clusters, that needs i
ntercellular adhesion. A specific polysaccharide antigen termed
polysaccharide intercellular adhesin (PIA), that is encompassed i
n intercellular adhesion and biofilm accumulation and is chemi
cally connected to PS/A, has been noticed and analysed in staph
ylococci. Tn917 mutants lacking PIA were not able to accu- mula
te in multilayered cell clusters. The icaADBC operon that mediat
es cell clustering and the intercellular adhesin synthesis in S. epi
dermidis has been cloned and sequenced. [39,40] Later, three su
pplementary gene loci were recognized, that have a manage or in
direct manipulating impact on expression of the synthetic genes
for PIA and biofilm formation. In a mouse ideal of subcutaneou
s external body infection as [41] [38]
well as in a rat ideal of CVC-associated infection, a PIA-negative
mutant was shown to be considerably less virulent than the isoge
nic wild-type strain. A PIA/haemagglutinin-positive S. epidermi
dis strain was considerably extra probable to cause a subcutaneou
s abscess than its isogenic PIA/haemagglutinin-negative mutant a
nd was considerably less probable to be eliminated from the inoc
ulation locale by host defence. Furthermore, the wild-type strain
was discovered to adhere to the implanted catheters extra plentifu
lly than the PIA/haemagglutinin-negative mutant. [43] In an inve
stigation projected to discover the pathogenic properties of S. epi
dermidis strains ob- [42,43]
tained from blood of patients alongside FBRI, a forceful associat

ion was noticed amid pathogenesis and both biofilm formation an
d attendance of the ica gene cluster. [44] Most presently, it was s
hown that induc- tion of biofilm formation might be completely i
nhib- ited by chloramphenicol, that given at a afterward period
of biofilm accumulation additionally inhibited further progres
s of preformed biofilm. This indi- cates that constant translation o
f an supplementary, icaADBC-independent factor is needed for t
he expression of a biofilm-positive phenotype. [45]
Other factors such as the 140 kDa extracellular protein AAP (acc
umulation-associated protein) additionally seem to be vital for ac
cumulation and biofilm formation. [46] AAP, that is lacking in a
n accumu lation-negative mutant and detectable merely in ex trac
ellular produce from bacteria grown below ses sile conditions, wa
s shown to be vital for accu mulative development in precise S. e
pidermidis strains on polymer surfaces. Of 58 CoNS learned,
55% were 140 kDa antigen-positive and produced momentous ly
larger numbers of biofilm than the supplementary strains that we
re 140 kDa antigen-negative. An antiserum specific for AAP inh
ibited accumulation by up to 98% of the wild-type strain. [46]
Taken jointly, the factors delineated here lead to the consequence
that bacteria, chiefly staphylococci, are able to adhere quickly to t
he external of a external body. Across the pursuing accumulation
period, the bacteria proliferate to form multilayered cell clusters
on the external of a health device. The attendance of such colossa
l adherent biofilms on the surfaces of external bodies, chiefly on
explanted intravascular catheters, has been clarified by scanning
electron microscopy. [26,47]
Intercellular signalling, frequently denoted to as quorum detectin

g, has been shown to be encompassed in biofilm progress by cou
ntless Gram-positive and -negative bacteria such as Streptococcu
s mutans, Burkholderia cepacia and Pseudomonas aeruginosa. Fo
r example, below precise conditions, a quorum-sensingdefective
mutant of P. aeruginosa is in difference to its parent strain in
capable to
form a exceedingly differentiated biofilm structure. The S. aureus
quorum-sensing arrangement is encoded by the accessory gene w
atchdog (agr) locus that con tributes to virulence in ideal biofilmassociated infections. Most presently, it was shown that, below a
little conditions, disruption of agr expression had no discernible i
mpact on biofilm formation, as below others it whichever inhibite
d or enhanced biofilm formation. Below those conditions wherea
s agr expression enhanced biofilm formation (tested in a rotatin
g-disk reactor), biofilms of an agr signalling mutant were chiefly
sensitive to rifampicin but not to oxacillin. [49] [48]
The clinical experience alongside polymer-associated infections r
eveals that the host defence mechanisms frequently seem to be i
ncapable to grasp the infection and, in particular, to remove the
micro-organisms from the infected polymer device. In supplemen
t, antibacterial chemotherapy is oftentimes not able to remedy t
hese infections even though the use of antibacterials alongside pr
oven in vitro attention (see serving 3.3). Thus, the biofilm could
protect the embedded bacteria opposing host reply mechanisms a
s well as opposing antibacterial agents. [50,51]
Management of Health Device Associated Infections :

General Considerations
Whenever an infection of an indwelling or im planted external bo

dy is distrusted, a finished decision has to be addressed: whether
to remove the external body and/or whether to onset computed a
ntimicrobial treatment. Replying the pursuing key inquiries could
aid the physician to grasp these infections adequately established
on a rationale approach. 1. Is an FBRI a plausible explanation for
the patients signals (e.g. fever, skin inflammation at the exit loca
le, soft tissue inflammation alongside the tunnel of an implanted
catheter, septic thrombophlebitis)?
2. Are there each chance factors predisposing for FBRI (e.g. neut
ropenia, malignant haematological disor ders, AIDS, kind of cath
eter)? 3. In that clinical situation is the patient (e.g. sepsis, pregn
ancy, premature infant)? 4. In the light of a probable necessity to
remove the external body, how vital is the health mechanism for
the patient regarding: (i) the survival of the patient (e.g. cardiac
mechanisms or highly needed cath eters, such as tunnelled Brov
iac-Hickman-type cath eters or totally implantable venous admiss
ion mechanisms [i.e. ports] for intravenous management of vital
medications and parenteral nutrition); (ii) prosthetic therapy (e.g.
prosthetic joints, lens); (iii) optimal intravenous request of fluids
, medications and blood produce (e.g. all kinds of vascular prost
heses; haemodialysis shunts); and (iv) cosmetic and reconstructi
ve surgery? 5. Which diagnostic methods ought to be requested t
o confirm the diagnosis? 6. Is computed antimicrobial therapy vit
al and, if so, that antibacterials ought to be given?
Several comprehensive reviews on the clinical association of inf
ections due to an increasing
palette of health mechanisms have been published concentrating
on disparate aspects considering the removal of the infected mec
hanism, antimicrobial therapy and on supplementary procedures t

o notice and stop complications associated alongside FBRIs.
[5,9,10,52-63]
Removal of Device
The optimal treatment of a FBRI is the removal of the infected m
echanism after probable and its substitute if yet needed. This is th
e therapy of choice, exceptionally for easy-to-change mechanism
s such as shortterm peripheral catheters. [5,9] Although of the kin
d of mechanism, removal of implanted mechanisms is suggested
after the patient displays signals of harsh sepsis, septic phlebitis a
nd septic surprise (table III). Furthermore, catheters ought to be r
emoved in patients alongside bacteraemia persisting extra than
4872 hours. In supplement, attendance of innate skin or soft tiss
ue infections (e.g. tunnel infection, gross purulence at the exit sit
e), metastatic complications (e.g. endocarditis, osteo- myelitis, se
ptic thrombosis) and/or relapse of infection afterward antibacter
ial therapy has been discontin- ued ought to lead to removal of th
e device. In addi- tion, innate debridement at the exit locale of a h
ealth mechanism ought to be believed if a subcutaneous abscess
or comprehensive tunnelitis is present. The removal of the mecha
nism is usually vital if micro-organisms are remote recognized t
o be tough to eliminate or to be of elevated virulence such as S. a
ureus, P. aeruginosa or supplementary non-fermenter, mycobacte
ria and yeasts. [64-67]
Studies have shown that long-term tunnelled catheters (mainly ha
emodialysis catheters) could be exchanged prosperously alongsi
de guidewire in patients alongside uncomplicated CRBI and no si
gnals of exit, tunnel tract or pouch infection. [68-71]
Salvage of Mechanism and Treatment alongside Antimicrobi

al Agents
Removing the infected health mechanism is not always probable,
facile to present and/or lacking chance and, consequently, salvag
e of the mechanism is from time to time the favored option. In pa
rticular, FBRIs associated alongside long-term or perpetual cathe
ters (such as Hickman-type catheter or Port-a-Cath) are frequently indulged prosperously through the line (table III). [4,72,73]
After a biofilm has industrialized on an implanted health mechani
sm it is tough to delight such infections because of considerably c
ut levels of susceptibility to antimicrobial agents (some 10 to
1000 periods less) and lower levels of phagocytosis comparative
to the levels of confrontation and phagocytosis for their planktoni
c counterparts (see pathogenesis, serving 2). [74] Thus, supraphy
siological concentrations of antibacterial agents could be needed
to remove the micro-organisms embedded in biofilms. [75] As
shown in a number of experimental FBRIs, the pharmacokinetic
parameters are adjusted and do not correspond to the efficacy of
antibacterial delight ment in vivo after a external body is implant
ed. These adjustments are seeming if mouse model-based after
math of S. aureus-caused intra-abdominal abscess
surrounding intraperitoneally allocated silicone cathe ter indulged
by meticillin and gentamicin are analysed. [76] Whereas both ag
ents displayed forceful results in vitro in time-kill studies on bact
eria colonising catheters seized out of infected mice and on cathe
ters contaminated in vitro, merely poor aftermath were noted in v
ivo, even though elevated innate concentrations (greater than mi
nimum inhibitory concentration [MIC] for at least 72 hours) of

meticillin and elevated top concentrations of gentamicin (>13 g
/ mL). The wreck was not provoked by progress of antibacterial
confrontation or affected by protein con centration, pH or innate
attendance of inhibitors of antibacterials in the pus. Of significa
nce, antibacterials administered in subinhibitory concentrations c
ould impact the mechanisms of adherence and slime creation, ex
ceptionally in staphylococci, for example, managing to higher pol
ysaccharide intracellular adhesin creation or to increased expressi
on of fibronectin-binding proteins. [77-79] The distinct condition
s encircling a external body have accompanied the find for altern
ative requests of antibacterials such as lipid-based sustained- dis
charge formulations. Roehrborn et al. delineate the use of such b
iodegradable, innately injectable formulation of amikacin in a m
ouse ideal in that Teflon 1 pipes were subcutaneously implante
d and challenged by inoculation of S. aureus. Whereas treatment
alongside innate or systemic free amikacin had no result, the nu
mber of infected external bodies was decreased from 86% to
25% (p = 0.02) pursuing treatment alongside encapsulated amika
cin formulation, and log cfu (colony growing units) each gram of
tissue [80] was considerably cut from 4.8 0.9 to 1.3 0.6. Typi
cally, early treatment of catheter-related bacteraemia is managem
ent of systemic antibacterials. Additionally, after a catheter-relat
ed infection is documented and a specific pathogen is identi- fie
d, antibiotic-lock therapy ought to be believed if salvage of the
catheter is necessary. It is notewor- thy that recommendations for
the treatment of
medical device-associated infections are established almost com
pletely on observational studies, animal models, case reports and
expert opinion rather than on the aftermath of appropriate clinical

trials.
The seven papers included in this thesis all employ the biomimetic m
ethod to enable precipitation of HA on crystalline TiO2 surfaces. As
displayed in Figure 3, the papers focus on methods for depositing func
tional surgical implant coatings; TiO2 and HA, the use of biomimet
ically deposited HA (HA-B) coatings as drug delivery vehicle as well
as the evaluation of the bioactive, biomechanical and bactericidal prop
erties of both coating types.
This thesis is based on the following papers, which are referred to in th
e text by their Roman numerals.
Lilja, M., Welch K., strand M., Engqvist H., Strmme

M. (2012) Effect of deposition parameters on the photocata
lytic activity and bioactivity of TiO2 thin films deposit
ed by vacuum arc on Ti-6Al-4V substrates. J Biomed
Mater Res B, 100B (4):107885
II
Lilja, M., Forsgren, J., Welch K., strand M., Engqvist

H., Strmme M. (2012) Photocatalytic and antimicrobial pr
operties of surgical implant coatings of titanium dioxide de
posited through cathodic arc evaporation. Biotech Lett,
34(12):2299-305
III
Lilja M., Lindahl C., Xia W., Engqvist H., Strmme M.

(2013) The Effect of Si-doping on the Release of Antibioti
c from Hy- droxyapatite Coatings. J Biomater Nanobiotech

, 4(3):237-41
IV
Lilja M., Srensen J.H., Brohede U., strand M., Procte

r P., Arnolid J., Steckel H., Strmme M. (2013) Drug loadi
ng and release of Tobramycin from hydroxyapatite coated
fixation pins. J Mater Sci: Mater Med, 24 (9):2265-2274
Srensen J.H., Lilja M., Srensen T., strand M., Procte

r P., Strmme M., Steckel H. (2013) Co-precipitation of To
bramycin into biomimetically coated orthopedic fixation pi
ns employing sub-micron thin seed layers of hydroxyapatit
e, submitted
VI
Srensen J.H.*, Lilja M.*, Srensen T., strand M., Procte

r P., Strmme M., Steckel H. (2013) Biomechanical and A
ntibacteri- al Properties of Trobamycin Loaded Hydrox
yapatite
Coated
Fixation
Pins,
submitted
Materials and Methods

VII Lilja M.*, Srensen J.H.*, Srensen T., strand M., Proct
er P., Strmme M, Steckel H. (2013) Impact of biomechan
ical forces on the release kinetics of hydroxyapatite coated
fixation pins, J Biomater Nanobiotech, 4(4):343-50
Figure 3. Overview of the studies presented in t

his thesis.
The bioactive surfaces onto which HA-B coatings were deposited were
made using CAD. Paper I investigated the deposition parameters to al
low for deposition of crystalline TiO2 coatings consisting of anatase
or rutile phase or a mixture thereof. Additionally, the bioactive and ph
otocatalytic properties of these coatings were evaluated. Coating serie
s with variation in deposition time (2; 5; 20 min), temperature (320;
600 C), bias voltage (-60; -120
Materials and Methods

V) and oxygen flow (50-800 sccm) were performed. Paper II focus
ed on
the bactericidal effects of TiO2 photocatalysis of anatase phase do

minated
TiO2 coatings with a thickness of approximate
700 nm.
In Paper III to VII, anatase phase TiO2 coatings with a thickness o
f 500
nm served as bioactive surfaces to enable deposition of HA-B coatings
. Following a cleaning procedure in acetone, ethanol and distilled water
after PVD deposition, the coated substrates were placed in plastic cont
ainers containing either pure, Si-enriched or antibiotic-enriched PBS
for various time periods, see Table 1. The temperature was kept eith
er at 37 C to mimic body surroundings (Paper I, IV to VII) or incr
eased to 60 C to impact the morphology as well as the growth rate of
the HA coatings (Paper II, VI). In Paper V, elevated PBS temperatur
e was used to deposit - as a first step - a thin, crystalline HA layer ont
o the TiO2 coated substrates. This layer provided small HA crystals
with large surface area and thereby served as a seed layer for the follo
wing precipitation of an antibiotic containing HA coating.
Plasma sprayed HA coated fixation pins served as reference substra
tes in Paper IV. Examples of the coated samples used in Paper IV to
VII are presented in Figure 4.
Figure 4. Overview of samples used in Paper I

V to VII.
Table 1. Description of the samples used in Paper I and Paper III to VII
Pape
III
IV
Plates
V
Disc
VI
VII
Disc
Plate
(20*20 m
Fixation pi
Fixation pi
m), Fixatio
( 9 mm
ns
ns
( 9 m
(20*20 m
n pins ( 4
),
( 4 m
( 4 m
m) 5
Ti grade
m) 4
Ti grade
mm, Ste
Stainless
90 mm*30
m
el
Fixation
Ti gradepi
ns
5 (discs)
m,
SS
90 mm*30 m
m,
SS
90 mm*30 m
m)
(SS)
Anatase
( 4(SS
m
Pins
Anatase
m,
)
m)
m)
Anatase
Anatase
r
Geometry
Substrate Materi
al
Anatase, rut
Dominating Ti
ile and th
O2
eir mixtur
Polymorp
Solution
h
Temperature [C
es
Dulbeccos
P
BS
Anatase
90
mm*30 m
1)Dulbecco
Si-enriched
Dulbeccos P
37
BS (2mM)
60
Dulbeccos P
PBS
BS
1; 7
Dulbeccos PB Dulbeccos P
S
BS
37
2)Dulbecc
1)
37;
60
os1)PBS
603 +
Tobramyci
2)2)6
]
Time [d]
m)
s
n
37
37
UV Treatment and Photocatalytic Activity Testing

An UV-A diode (NCSU033B, =365 nm, Nichia, Japan) served as lig
ht source for UV illumination during PCA testing in Paper I and II an
d during the evaluation of the antibacterial properties of the TiO2 coati
ng in Paper II. The intensity of the UV light was measured with a UV
light meter (UV-340, Lutron). The PCA of the TiO2 coatings in Pape
r I and II was evaluated by measuring the degradation of Rhodamine
B dye as a function of illumination time. A UV photospectrometer
(UV-1800, Shimadzu) was used for adsorption measurements in
order to evaluate the degradation of the inorganic indicator molecu
le.
Bacterial Viability Analysis
Resazurin was employed as an indicator to evaluate the viability

of S. epidermidis in Paper II. As a result of chemical reactions due
to bacterial cell growth, this dye changes from non-fluorescent form
(blue) to resorufin, a highly fluorescent form (pink). The fluorescence
measurements were performed with an Infinite M200 plate reader (Tec
an). A standard curve was made by n-fold dilution of the bacteria susp
ension to allow quantitative determination of the viability after UV trea
tment.
The biocompatibility of the TiO2-HA coating system used as
drug delivery vehicle was evaluated in Paper VI by cell viab
ility tests.
Endothelial cells and primary osteoblasts were seeded both on TiO2 a
nd HA coated Ti grade 5 discs. The cellular viability and morphology
of the cells were analyzed after 3 days of culture by Calcein AM staini

ng.
Antibiotic Loading Procedures
In Papers III, IV, VI and VII the antibiotics were loaded into the H
A coatings by adsorption, whereas Paper V and VI evaluated incorpo
ration of Tobramycin via co-precipitation. Table 2 provides an overvie
w of the antibiotics used and the drug loading conditions employed.
In Paper III, it was investigated whether the antibiotic release pr
ofile
could be impacted by the use of ion substituted HA. For this pur
pose, Cephalothin was incorporated into the pure HA-B and SiHA-B
(deposited from Si-enriched PBS) coated samples via soaking and the
release of the antibiotic from these two sample types was compared.
Paper IV focused on the effect of drug concentration, soaking ti
me as well as the physical conditions (temperature and pressure) unde
r loading on the drug incorporation and release properties. HA-B co
ated fixation pins were exposed to stock solutions of three different c
oncentrations for various time periods. Furthermore, the impact of incr
eased temperature (90 C) or elevated pressure (6 bar), or a combin
ation of both, under loading was investigated using an antibiotic con
centration of 20 mg/ml. All samples were dried for 24 hours at 37 C a
fter loading. The subsequent drug release was studied and compared to
the release profiles obtained from plasma sprayed counterparts expose
d to the same loading procedures.
In Paper VI and VII, Tobramycin was loaded into HA coated sample

s by two different loading methods. The samples were either placed in
containers with a drug solution at room temperature for 5 min or put
into a stainless steel tube together with the 90 C heated antibiotic con
taining solution under an applied pressure of 6 bar. Drug incorporatio
n via co-precipitation was employed in Papers V and VII. For the pre
paration of those samples, the TiO2 coated pins were in a first step coa
ted with a thin HA startlayer through immersion in 50 ml PBS at 60
C, followed by immersion in antibiotic containing PBS for 6 days at
37 C. The possibility to tailor the drug release from co-precipitated
coatings was studied by additional loading by adsorption of thi
s antibiotic containing coating structure. For this step, the co-precipit
ation-coated samples were placed in a solution with a drug concentrat
ion of 20 mg/ml for 5 min.
After the last time point measured for the antibiotic release in Pape
rs IV to VII, HPLC analysis was performed on solutions containing t
he in pH 2 dissolved coatings to determine the amounts of drugs r
emaining in the coatings.
Table 2. Drug loading parameters employed for antibiotic incorporation into HA coatings
Paper
Loadin
Antibiotic
g meth
ation
Concentr
[mg/ml]
od
Temp-
Loadin
Pressur
erature [o
g time
C]
[min]
[bar
]
III
Adsorption
Cephalotin
Adsorption,
Tobramycin
37
40 (IV)
RT
60
1
IV, VI,
V)
5; 15; 60 (I
VII
IV
(Load-RT)
Adsorption,
Tobramycin
IV
1 (Load-C)
Adsorption,
Tobramycin
20
RT
IV
6 (Load-P)
Adsorption,
Tobramycin
20
90
1 (Load-HT)
2020;
(VI,VII)
4;
40
RT
5 (VI,
5 VII)
IV, VI
Adsorption,
5
VII
Tobramycin
6 (Load-PHT)
Tobramycin
Co-precipitation
20
90
0.5; 1
37; 60
1
4; 20;40
37
6d
Biomechanical Insertion Tests
The biomechanical properties of HA-B coatings deposited on TiO2 c

oated fixation pins were evaluated in Paper VI by insertion tests into
bone substitute materials. Renshape BM5166 was chosen to simulat
e insertion into cancellous bone, while low density polyurethane fo
am (25 PU) was used to reflect spongy bone quality.
Figure 5. Schematic set up for insertion tests of HA coated fixation

pins into bone substitute materials.
As shown in Figure 5, the insertion materials were fixated to simulate a

bone with single cortex. The samples were inserted without predr
illing at a rotation speed of 10 rpm and with an axial force of
100 N (Renshape BM5166) and 50 N (25 PU), respectively. The coat
ing performance was evaluated by analyzing the insertion torque, m
aximum rising temperature and drilling time needed for an insertion
depth of 23 mm. Three different HA-B coating types, with variation
in coating thickness and morphology were evaluated.
In Papers VI and VII, the insertions of antibiotic loaded and co- pr
ecipitated pins into 25 PU material were performed manually.
Sample Characterization
A more detailed description of the characterization techniques used ca

n be found in the Materials and Method sections in the papers of this
thesis.
X-ray Diffraction (XRD) was employed to characterize the microstr
ucture of as-deposited TiO2 and HA-B coatings in Papers I, III
and IV. The effective grain size of the as-deposited TiO2 coatings in
Papers I and II was determined from the full width at half maximum
(FWHM) of the XRD peaks using the Scherrer-equation [63]:
where L is the effective grain size and the wavelength of the X-rays.
The bioactivity of the different TiO2 coatings in Paper I was evalua
ted by Scanning electron microscopy (SEM) images of the surfaces aft
er two different immersion times in PBS. SEM was further used to eva
luate the coating thicknesses of the as-deposited TiO2 coatings in Pap
ers I and II and to study the morphology, surface coverage, coatin
g thicknesses and co- precipitated coatings investigated in Papers II
I to VII. In Papers VI and VII, SEM was employed for determini
ng the performance of the HA coatings under study, both after inser
tion into bone model materials and after scratch testing.
The surface topography of biomimetic and plasma sprayed deposite
d HA coatings in Paper III was examined by a white light interferom
eter. This method allowed for obtaining three-dimensional surface map
s of the coating types used for the drug loading and release experimen
ts. In Paper VI, the impact of biomechanical forces on the HA coating
quality was studied by an optical 3D micro coordinate measurement s
ystem. This 360 measurement of the HA-B coated fixation pin after i
nsertion into bone model material enabled the determination of high s
tress areas over the entire thread of the pin as well as to visualize cha
nges in the HA coating properties after insertion.
The coating adhesion of HA-B coatings with various thickness and
morphology towards the underlying TiO2 surface was evaluated by s
cratch testing on planar stainless steel plates. A 500 m spherical diam
ond indenter was used under progressive loading conditions.
The penetration of Tobramycin into the HA coatings under diff
erent loading conditions was measured with Glow discharge optica
l emission spectroscopy (GDOES). Quantitative chemical in-depth pr
ofiles of the characteristic elements nitrogen and carbon were obtained
by analyzing the chemical composition of antibiotic containing sam
ples from the surface towards the substrate. An HA-B coated plate wi
thout any Tobramycin served as reference.
Drug Release Analysis and Antibacterial In Vitro Tests
The drug release of Cephalotin incorporated into both pure HA and Si

- substituted HA coatings was investigated in Paper III by means of
UV- visible light spectroscopy (Shimadzu UV-1650pc). The conce
ntration of Cephalothin in the release medium was determined by me
asuring the absorbance of light transmitted through the solution with a
characteristic adsorbance wavelength for the drug molecule under stu
dy.
High performance liquid chromatography (HPLC) was employed in
Papers IV to VII to measure the amounts of Tobramycin incorpora
ted in and released from the samples. The method is based on pre-colu
mn derivatization of the aminoglycoside antibiotic and UV-detection
(330 nm).
In Paper IV, it was investigated whether physical parameters u
nder
loading could impact the antibiotic release profile, while Paper VI foc
used on the effect of HA coating thickness and coating morphology o
n the drug loading and release properties. The path of drug incorporati
on via co- precipitation was followed in Paper V. In Paper VII, the im
pact of insertion into bone model materials on the drug release profiles
was investigated. The obtained release profiles were compared to thos
e of mechanically untreated counterparts.
The bactericidal efficiency of Tobramycin incorporated into HA co
ated fixation pins was evaluated in Paper VI. For this purpose, modifi
ed agar diffusion tests were carried out by inserting antibiotic loaded p
ins, as described earlier, into Petri dishes containing 40 ml of steril
e Caso agar media and 5 ml of S. aureus suspended media. HA coate
d pins without Tobramycin served as reference. The petri dishes wer
e incubated at 35 C for 18 hours and the inhibition zones around the
pins were measured and photographed. After documentation of the re

sults from the first time point, the pins were rolled out over a fresh C
aso agar plate and incubated as previously described. After 24 hours, t
he pins were transferred to a fresh, germ suspended agar plate and
exposed to the incubation conditions described above. This proce
dure was repeated until no inhibition zone around the implant coul
d be observed.
Bioactive, Antibacterial TiO2 coatings

Microstructure, Bioactivity and Biocompatibility
Deposition of crystalline TiO2 coatings on various substrate material

s was accomplished using CAD. In Paper I, the impact of deposit
ion time, - temperature, bias voltage and oxygen flow profile
on the TiO2 microstructure was evaluated and the samples of each
deposition series were denoted as CAD time, CAD temp, CAD bias an
d CAD gradient. As obvious from the summary presented in Table 3,
variations in deposition time influenced the microstructure evolution of
the arc deposited coatings.
Table 3. TiO2 coating deposition parameters and structural c

haracteristics
Sample Depositi
Bia
Temp
TiO2 t
- erat
hicknes Dominati Calculat

ng pha ed grain
s (nm)
on time
ure
(min)
(V
(C)
sea
sizeb
)
2min
CAD time
-60
320
70
R(110)
-60
320
150
A(101)
20
-60
320
500
A(101)
20
5min
CAD time
30
20min
CAD time
35
30min
CAD time
30
-60
320
700
A(101)
20
-60
600
450
R(110)
20
-120
320
650
A(101)
45
CAD
temp
35
CAD bias
32
CAD
20
gradie
26
-60
320
250 (600)c
R(110)
nt
a Measured using XRD, where A and R denote the anatase and ruti
le phases, respectively
b Determined from Scherrer
-Equation
c total coating thickness is ~600 nm, consisting of a metallic phase of
~350 nm and a gradient
oxide
phase
of
~250 nm
Rutile phase was found to be present near the substrate interface for C
AD time depositions, while the amount decreased with increasing
deposition time [64,65], Figure 6 a. Increased deposition temperature
(CAD temp), as well as enhanced bias voltage (CAD bias), provided
the activation energy
needed to form rutile phases [66,67] and resulted in lower anatase to r

utile phase ratios compared to 20 min CAD time coatings. Increasing t
he oxygen flow throughout the deposition process (CAD gradient) res
ulted in a coating structure consisting of high amounts of rutile phase,
Figure 6 b.
Figure 6. Diffractograms of CAD time and CAD gradient series (le

ft panel) and SEM images of these coating types after immersion in P
BS for 1 day (middle panel) and 7 days (right panel), respectively.
Both anatase and rutile phases of crystalline TiO2 are known to be bio
active [21,24,25,39]. The presence of anatase phase [13,70] and also s
mall crystals offering a high surface area [71] have been shown to pro
mote HA nucleation on TiO2 surfaces. The bioactivity of the as-depo
sited TiO2 coatings was evaluated by the appearance of HA formatio
n on the surfaces after being immersed in PBS for 1 day and 7 days at
37 C, respectively. SEM images of HA nucleation and growth on CA
D time (Figure 6 a;1-4) and CAD gradient coatings (Figure 6 b;1-2) re
vealed the appearance of HA crystals on all surfaces after only 1 day i
n PBS. The crystal surface structure of CAD gradient coatings with s
mall, essentially rutile, Ti dioxide grains or essentially anatase 20
min CAD time coatings facilitated enhanced HA formation after
1 day in PBS (Figure 6 b;1) compared to microstructures with mixtu
res of these two polymorphs, i.e. the 5 min CAD time coating (Figure
6 a;1). Differences in the initial growth rate appeared to be of minor
impact after a week of immersion in PBS, where a continuous layer w

as present on all TiO2 coatings.
The response of both outgrowth endothelial cells and primary osteob
lasts
was investigated in Paper VI to further asses the biocompatibility of i
mplant surfaces functionalized with crystalline TiO2 with or without H
A-B coatings. As obvious from Figure 7, both cell types were viable a
nd firmly attached to both HA (Figure 7 a,c) and TiO2 (Figure 7 b
,d) coated sample surfaces. These findings provide a first proof of the
biocompatible properties of these coating materials and make both sur
face modifications suitable choices to improve the osseoconductive pr
operties at the interface between implant and bone.
Figure 7. Calcein-AM viability assessment of outgrowth endothelial c

ells (OEC) (a,b) and primary osteoblasts (pOB) (c,d) on HA-B (5m) c
oatings (a,c) or 20 min CAD coated (b,d) discs after 3 days of culture.
Photocatalytic and Antibacterial Properties
The PCA of the as-deposited coatings was evaluated by measurin

g the degradation of Rhodamine B, which served as a PCA indicator
molecule. From all TiO2 coating types under study, those with do
minating anatase phase and with preferably smaller anatase grain size
s were demonstrated to promote higher PCA, as displayed in Figure 8
a. In agreement with literature [70,72], PCA was found to increase wit
h increasing coating thickness up to a coating thickness of about 250 n
m. Nevertheless, the highest photocatalytic
reaction rate, k, was measured for the CAD gradient coating, Figure 8
b. Increasing anatase contents in the microstructure of TiO2 coatings
has been shown to enhance photocatalytic reaction rates [73]. Small gr
ain sizes can contribute towards enhanced separation of the electrons
and holes produced in the photocatalytic process [74,75] and can furth
er offer a shorter transportation length for the electron-hole pairs from
the grain interfaces towards the surface [76], which may account for e
nhanced reaction rates for fine grained coatings.
Figure 8. PCA of as-deposited TiO2 coatings measured as Rhodami

ne B concentration versus time recorded in a solution containing the di
splayed samples under UV illumination (a) and degradation rates (b) o
f Rhodamine B under UV light illumination.
In Paper II, TiO2 photocatalysis was demonstrated to provide a bacte

ricidal effect against S. epidermidis. For this study, bacteria suspensio
n was spread over the surfaces of TiO2 coated discs and Ti grade 5 ref
erence discs prior to photocatalytic treatment with UV light. UV dos
es ranging from 0 to 16 J were applied to the surface. The viability o
f the bacteria was evaluated with an MAA incorporating resazurin as v
iability indicator. The reduction in bacteria viability as a function of
UV dose is shown in Figure 9. It can be seen that a clinically relevan

t UV dose of 2.4 J, corresponding to a illumination time of 2 min, lea
ds to a 90 % reduction of viable bacteria for TiO2 coated samples. Thi
s reduction is attributed to the formation of radical oxygen species at t
he TiO2 surfaces, which killed the bacteria present on the sample surf
aces. Higher UV doses (>3 J) result in decreasing viability values for r
eference samples, which can be related to the bactericidal effect of the
UV light alone [57].
Figure 9. Number of viable bacteria on TiO2 coated and Ti grade 5 i

lluminated surfaces as a function of UV light dose, normalised wi
th respect to the tested bacteria concentrations. Error bars show the s
tandard deviation of 3 measurements.
In summary, the large scale production method CAD was demonstrated

to be suitable for making various crystalline TiO2
coatings of
high purity possessing not only bioactivity but also on-demand antiba
cterial functions. The results of the studies carried out on samples pro
duced with this method showed that surface microstructure and che
mistry are important factors impacting the initial stages of HA form
ation on TiO2 surfaces in vitro. The results demonstrated that the use
of crystalline TiO2 and HA coatings could be used to functionalize i
mplant surfaces for biomedical applications. The bioactivity and bioc
ompatibility of these coatings are believed to contribute towards impr
oving the bone healing process and thereby increasing the long term st
ability of the implant. The photocatalytic properties of TiO2 further

encourage the use of these coatings as on-demand antimicrobial su
rface enhancers in order to combat or reduce implant related infections.
Biomimetic HA Coatings as Carrier for Antibiotics
In order to prevent and control implant related infections, local antibio

tic delivery presents a straight forward approach to administer drugs di
rectly at the bone infected site and without reaching systemic toxicity l
evels of the drug itself [58,68]. To obtain an optimum release profile
[6], comprising a high initial release rate during the first hours, fol
lowed by a controlled release during the next days, the impact of H
A coating properties (Papers III, VI) and loading conditions (Paper
IV) on the release kinetics were evaluated. A novel loading method
to incorporate and release clinically relevant amounts of antibiotic
into biomimetic and plasma sprayed HA coatings was developed (P
aper IV).
In Paper IV, the drug loading and release properties of HA-B and pl
asma
sprayed HA (HA-P) coated fixation pins were compared. The impact o
f drug loading time, drug concentration, pressure and temperature on r
elease properties were evaluated by testing different drug loading con
ditions, as detailed in Table 2. For all loading methods tested, the relea
sed concentration of Tobramycin was measured to be above the MIC
of S. aureus [77] for all sample types during each time interval under s
tudy. As can be seen from the release profiles in Figure 10, loading by
adsorption under room temperature and atmospheric pressure (Ref-R
T) resulted in an initial burst release for both HA coating types. Nevert
heless, the nanoporous structure of HA-B coatings demonstrated super
ior drug penetrability, which is reflected by a prolonged sustained rele
ase over a time period of 2 days. In contrast, the rather dense and com
pact structures of HA-P samples limited the penetration depth making
only superficial adsorption possible and elution of the entire antibiotic
content occurred after only 15 min.
Antibiotic incorporation under elevated pressure (6 bar) and temper

ature
(90 C) (Load-PHT) was shown to be a successful adsorptive loading
procedure for fast-loading and slow release, ensuring a relea
se of Tobramycin above the MIC for S. aureus for 8 days from H
A-B coatings with various morphology and thickness, see Figure 10 a
nd Figure 12. Simi- larly, the release periods from HA-P coatings wer
e extended from 15 min to
2 days, Figure
10.
The effective incorporation of Tobramycin into HA-B coatings was
indicated via GDOES analysis, Figure 11. Elevated pressure in combi
nation with an increased viscosity and diffusion coefficient of the drug
containing solutions at elevated temperature resulted in an enhanced
penetration depth of the drug into the denser part of the coating structu
re at a depth of about 34 m. Loading under room temperature and atmospheric pressure (Loa
d-RT)
was found to be mainly characterized by superficial adsorption with a
peak concentration for both carbon and nitrogen at a coating depth of a
bout 1 m.
Figure 10. SEM images of HA-B (a) and HA-P (b) surfaces and non-c
umulative amounts of Tobramycin released in 37 C PBS from HA-P a
nd HA-B coated pins from the Load-PHT series after being loaded for
5 minutes in a solution containing
20 mg/ml of the antibiotics at 90 C and 6 bar. Release results fr
om reference samples loaded during 5 minutes in similar solutions at a
tmospheric pressures and room temperature are incorporated. Error b
ars denote the standard deviation of 3
measurements. The average total amounts of Tobramycin released fro
m each coating type are also displayed.
Figure 11. Depth profiles of carbon (a) and nitrogen (b) of a HA-B sa
mple loaded with 20 mg/ml Tobramycin under the displayed loading s
eries. The profiles of an unloaded reference sample are also displayed.
The formation of surface area and HA crystal morphology during bi

omimetic coating deposition is not only of primary interest in terms of
the influence on the in vitro drug loading properties but also because o
f the impact of those parameters on the interactions with body fluids, p
roteins and cells in vivo [69]. A preferential adsorption of proteins and
cells on an implant coating can be expected to affect the bonding occu
rring between implant and bone after implantation.
In Paper VI, the impact of HA-B coating thickness and morpholo
gy on the drug loading and release properties was investigated. SEM
analysis of the HA coatings deposited at different temperatures showe
d that the morphology changed from plate-like crystals towards a net
work consisting of small spherical crystals with needle-like morph
ology with increasing temperature, see Figure 12 a,b. The release pro
files of HA-B_37 samples (obtained through immersion of TiO2 c
oated samples for various time periods in PBS at 37 C) with differ
ent coating thicknesses revealed that thicker coatings exhibited more
beneficial coating structure characteristics for incorporating and relea
sing greater amounts of Tobramycin compared to thinner counterparts,
Figure 12 c. Comparison of drug release properties of HA coatings wi
th similar thickness but different morphology, Figure 12 d, indicated t
hat also surface area and nanoporosity within the penetration dept
h of the drug present essential parameters for controlling the antibiotic
release profiles. The total elution of Tobramycin from HA-B_60 coati
ngs samples (obtained through immersion of TiO2 coated samples fo
r 6 days in PBS at 60 C) after only 4 h, when loaded under RT condit
ions, confirmed a denser and more compact coating structure. This stru
ctural difference most likely restricted the penetration depth of the dru
g solution and results in dominating superficial drug adsorption.
Irrespective of coating thickness and morphology, the PHT loa
ding method allowed tailoring the penetration of the drug into the inter
ior of the coating structures along with increasing the total amount
of incorporated drug compared to the corresponding RT loaded sample
s, see Figure 12 d.
To further influence the drug release profile by factors not onl
y influencing the surface-drug attraction but as well taking the bi
nding capacity and HA coating chemistry into account [78,79], the im
pact of Si- doping on the release of Cephalothin from HA-B coatings
was investigated in Paper III. The incorporation of Si-ions during bio
mimetic deposition contributed to form coating structures with larger s
urface areas and smaller crystal sizes [80,81] compared to the pure H
A-B complements. The SEM images of the topographies in Figure 13
a,b showed a flake-like morphology for both sample types [80] and c
onfirm further a more dense structure for HA-B coatings in contrast t
o the more porous appearing crystal network for SiHA-B coatings.
Figure 12. SEM images of HA-B_37 (a) and HA-B_60 (b) coatings an
d non- cumulative amount of Tobramycin released in 37 C PBS from
HA-B_37 coated (c) and HA-B_37 and HA-B_60 coated pins (d)
of indicated thickness after being loaded for 5 minutes in a solutio
n containing 20 mg/ml of the antibiotics under either room temperat
ure at atmospheric pressure or at 90 C and 6 bar. Error bars denote th
e standard deviation of 3 measurements. The average total amounts of

Tobramycin released from each sample type are also displayed.
Samples placed horizontally (h) in PBS during coating growth showed

a higher growth rate and also increased drug adsorption ability compar
ed to perpendicular (p) placed samples. The drug release profiles prese
nted in Figure 13 c show a fast release of the antibiotic within the first
10 min, followed by a slower continuous release period lasting for abo
ut 10 hours. Under comparable deposition conditions, SiHA-B coating
s exhibit an increased drug incorporation capacity and faster release pr
ocess compared to pure HA-B coatings. This difference can be explain
ed by the change in surface chemistry [82] and the negative surface ch
arge [83] developing when the HA structure is substituted by Si-ions.
As a result of this, the interaction between antibiotic and Ca-ions in th
e SiHA-B coatings is restricted [84] and the drug is repelled from the s
amples, as confirmed by the rapid release during the first 10 min, Figu
re 13 c. Prolonged release was obtained from pure HA-B coatings, wh
ich can be attributed to a preferential binding of Cephalothin to Ca-ion
s in these coating types.
Figure 13. SEM images (left panel) of HA-B (a) and SiHA-B (b) co
ated surfaces after an immersion time of 7 days in perpendicular positi
on (p) in PBS and Si- enriched PBS, respectively, and release curves (r
ight panel, c) presenting the initial (lower panel) and total (upper panel
) release period under study of Cephalothin released in room-tempered

deionized water per surface area for HA-B and SiHA-B in horizontal
(h) or p position.
The findings in Papers III, IV and VI show that it is possible to use

nanoporous HA-B coatings as carriers for antibiotics to obtain a contr
olled release of the incorporated drug over an extensive time period. T
he HA-B coating properties can be modified in various ways and
thereby add flexibility to the proposed local drug delivery concept. By
modifying the deposition conditions, it was possible to adjust the mor
phology, chemical composition, surface area and surface charge of th
e HA coatings and hence
impact the drug incorporation capacity and furthermore the release pro
per- properties. Altering the physical conditions under loading by adso
rption was shown to have a significant impact on the penetration depth
of the drug and, hence, influence the drug release time. The incorporat
ion of ions, that play a significant role in the biochemistry of bone
tissue, was shown to be a possible strategy to impact the drug affini
ty and drug uptake as well as to tailor drug release profiles. The amou
nts of antibiotics released in these presented studies were sufficient to
inhibit the growth of S. aureus, which is one of the main pathogens in i
mplant related infections.
These results provide a valuable outline for the design of implant su
rfaces aiming for a fast loading and controlled local drug adminis
tration. The combined use of bioactive ions and antibiotics facilitates t
he development of dual-activity implant surfaces that contribute
both towards tissue regeneration and the prevention of implant relate
d infections.
Antibiotic Incorporation via Co-Precipitation
Drug incorporation into porous HA coatings and calcium phosphate b

ased materials for local drug release is mostly accomplished by adsorp
tive loading methods using water soluble drugs [50-53,85,86]. Co-pr
ecipitation presents, in contrast, a single step coating deposition meth
od that allows for integration of the drug throughout the coating growth
.
In Paper V, it was shown that co-precipitation allowed producing
To- bramycin containing HA coatings on external fixation pins. Functi
onalizing the TiO2 coated pins in a first step with a thin HA startlayer
coating, Figure
14, was found to be a promising surface modification to overcome th
e - in
literature described - challenge of antibiotic induced inhibition of nucl
eation and coating growth in the presence of pharmaceutically relevan
t drug concentrations [53,87].
Figure 14. SEM image of an ion-milled cross section of the HA startla

yer after immersion in PBS for 3 days at 60 C.
Increased Tobramycin concentration in PBS was found to influence b

oth coating morphology and coating thickness. As displayed in Figur
e 15 a,b, co-precipitated coatings obtained from a solution containing

4 mg/ml antibiotic, denoted as Co-4, showed a flake-like morphology
, whereas a Tobramy- cin concentration of 20 mg/ml (Co-20) induced
the formation of smaller, spherical crystals. The total average coating t
hickness was measured to be ~
3-3.5 m for Co-4 samples and ~ 2-2.5 m for Co-20 sam
ples.
The release profiles, Figure 15 c, show an initial burst release withi
n the first 15 min followed by a slow, controlled release lasting for
12 days for Co-4 and for 8 days for Co-20 coated pins. Incorporation
of Tobramycin loaded by adsorption into the porous structure of Co4 samples, designated as Co-4/20, enabled the increase of the amount
of drug incorporated and released during the entire time period of 12
days. The antibiotic concentration was for all three sample types abo
ve the MIC for S. aureus [77] during each measured time interval.
Figure 15. SEM images of coating structures obtained after immersion

of HA startlayer coated pins in Tobramycin containing PBS for 6 days
at 37 C with a concentration of 4 mg/ml (a) and 20 mg/ml (b); and no
n-cumulative amount of To- bramycin released in 37 C PBS from Co4, Co-20 and Co-4/20 samples (c). The average total amounts of Tobra
mycin released from each sample type are also displayed. The error
bars indicate the standard deviations from 3 measurements.
GDOES measurements, Figure 16, indicated successful integration of

the antibiotic throughout the entire coating thickness. For co-precipitat
ed coatings both carbon- and nitrogen concentrations were found to

increase from the substrate interface towards the surface. The incorpor
ation of antibiotics even in the deeper sections of the coating structure
may account for the sustained release properties and the extended rel
ease time of co-precipitated sample types compared to those loaded by
adsorption.
Figure 16. Depth profiles of carbon (a) and nitrogen (b) of a Co-4 sam
ple. The profiles of an unloaded HA reference sample are also displa
yed.
In summary, co-precipitation presents a promising method to function

alize implant surfaces with an antibiotic releasing coating providing
a superior drug release profile compared to coatings loaded by adsorpt
ion [52,53]. The nanoporous structure of co-precipitated samples provi
des the option to further incorporate water soluble drugs by adsorpti
on and, hence, allows for designing of drug release properties with res
pect to clinical application. The controlled delivery of antibiotics with
concentrations above the MIC for S. aureus over a time period of 12
days is expected to provide an efficient bacterial effect to minimize t
he risk of implant related infections over a clinically relevant adminis
tration period.
Biomechanical and Antibacterial Properties of

Antibiotic Eluting HA Coated Implant Surfaces
The use of biocompatible and bioactive HA coatings as surface modifi

ca- tions on metallic implants has proven to be an effective way to enh
ance the bone-implant interface strength [88-90]. While mechanical pr
operties of HA constitute a limiting factor for load-bearing application
s [52,88,89], adhesive strength and the ability to withstand biomechani
cal forces during implantation are important coating characteristics
for the use of HA-B coatings as drug delivery vehicles.
In Paper VI, the impact of biomechanical forces on HA-B coating
performance was evaluated by insertion tests into bone model materi
als. Com- parison of the coating wear patterns of HA-B coatings dep
osited at 37 C and 60 C, denoted as HA-B_37 and HA-B_60, resp
ectively, indicated for all samples types a stress concentration at the p
in entry site and thread tops. These stresses generated coating flake-of
f irrespective of the quality of the model material and the HA coating t
hickness and morphology tested, as shown on the 5 m thick HA coate
d pin in Figure 17. The evolution of shear stresses may account for the
observed coating compression and smearing in the vicinity of the roots
and the crests, Figure 17 a,c.
Scratch tests confirmed that the interface between the TiO2 and the
HA-B
coating presents a critical factor with respect to the adhesive strength
of the
coating system. The scratch paths showed, for all samples under study,
preferential detachment of the HA-B coating from the underlying Ti
O2 coating, Figure 18, while the crystalline TiO2 coating exhibited
excellent cohesive and adhesive strength. Increased HA-B coating thic
kness seemed to have a negative impact on the adhesion strength, as e
videnced by similar critical loading forces obtained for different coatin

g thickness of HA-B_37 samples. Figure 18 b,c. However, for thin coa
tings in this study, the FNC values, describing continuous spalling of
the HA-B coating types under study, were greater than those values pr
eviously reported [91,92]. This highlights the bioactive properties of t
he TiO2 coating, giving rise to the formation of a promising chemica
l bond.
In Paper VI, bacterial inhibition tests indicated that the adsorption loa
ding methods tested (RT, PHT) were efficient for incorporating releva
nt concentrations of Tobramycin into HA-B coatings to inhibit bacte
rial growth of S. aureus. After 1 day, all antibiotic loaded samples reve
aled circular inhibition zones, Figure 19 (a,b; 2-4), as a result of the ra
dial diffusion of the antibiotic from the implant into the agar medium.
Roll-out tests further demonstrated efficient protection of the antibiotic
containing implant surfaces against early bacterial attachment, Figure
19 (c; 2-4).
Figure 17. 3D visualization images (a) and SEM images (b-d) of 5

m thick HA-B
coated fixation pins after insertion into 25 PU bone mo
del material.
Figure 18. SEM images of scratch paths created with a 500 m diamo
nd tip on HA- B_60 (a) and HA-B_37 (b,c) samples of indicated thick
ness. The scale bar in all panels is 20 m.
In contrast, HA reference samples did not reveal any inhibition effe

cts, as confirmed by clear bacterial growth on roll-out plates after 1 da
y incubation in agar, Figure 19 (a,b; 1).
The antibiotic release ensured a measurable antibacterial effect up t
o 6 days for both RT and PHT loaded samples, with no significant imp
act of the loading method on the bactericidal properties, Figure 19 d.
On the contrary, insertion of RT-loaded samples into bone model mate
rial (25 PU) prior to bacterial inhibition testing, denoted as RT_BML,
revealed a minor reduction in inhibition zone area and protection time
period compared to mechanically untreated complements.
Related to mechanical stability of HA-B coatings and the local relea
se of drugs from such, the question arises of what would happen at the
implant- bone interface in case of coating wear and loss. In Paper VII,
we investigated the impact of HA-B coating wear on the in vitro dru
g release properties. Antibiotic containing samples were inserted into
25 PU bone model material prior to the performed drug release studies.
Insertion induced coating wear resulted in partial fragmentation and
coating delamination, as obvious from the white discoloration of the
insertion material, Figure 20 a. The antibiotic containing coating loose
ning from the TiO2 covered implant surface seemed to remain in the b
one model material, Figure 20 b,c. The observed coating deterioration
followed from insertion created significant reduction of the amount of
drug released during initial burst, Figure 20 d,e. Notably, only minor e
ffects on the sustained release profile were observed and a release lasti
ng 5 days for PHT_BML and 8 days for Co-4_BML samples. The rel
eased amounts of Tobramycin were above the MIC for S. aureus for a
ll time points [77].
The results indicate that biomechanical forces occurring during inse
rtion influenced the initial burst kinetics in vitro. However, the observe
d reduction will most likely not prevail in vivo with respect to the dela
minated coating remaining within the synthetic bone structure. Hence,

the antibiotic release can be expected to not only eliminate bacteria dir
ectly at the implant interface but also at those areas where the coati
ng settles in the bone structure, viz. at the insertion point and at some
distance from the implant.
Biocompatibility of both TiO2 and HA-B coated surfaces was con
firmed by the adhesion of bone forming cells on both surfaces, Figure
7. Thus, potential HA-B coating delamination induced through insert
ion into bone in vivo may still be assumed to result in cellular attach
ment on the TiO2 surface. Hence, both surface coatings present suit
able surface modification to improve integration between implant and
bone.
Figure 19. Images of HA-B (5m) coated, RT loaded, PTH loaded and
RT_BML loaded pin after 18 hours of incubation in agar diffusion test
s against S. aureus (panels a and b). RT_BML loaded pin was addit
ionally inserted through a block of 25
PU foam. Panels c1-4 indicate the germs growing on fresh agar plates
after roll-out test after 24 hours. Panel d gives an overview of the inhib
ition zones of the different samples in accordance to the time period. T

he error bars indicate the standard deviations over 3 measurem
ents.
47
P a g e | 88
Figure 20. Photo (a) and SEM images (b,c) of 25 PU foam after pin insertio
n. The arrow in panel a presents the insertion direction (a). SEM images we
re taken at a depth of 2 mm from the pin entry point; Non-cumulative amou
nt of Tobramycin released in 37 C PBS from HA-B coated pins (d) after
RT and PHT loading in a solution containing 20 mg/ml of the antibiotics an
d following insertion into 25 PU foam (BML samples) and Co-4 coated p
ins (e) after insertion into 25 PU foam (BML samples). Release results
from mechanically untreated RT, PHT and Co-4 samples are incorporated
as reference. Error bars denote the standard deviation of 3 measurements. T
he average total amounts of Tobramycin released from each sample type ar
e also displayed.
P a g e | 89
To conclude, Tobramycin eluting HA coated fixation pins showed promisin

g bactericidal efficiency against S. aureus in modified agar tests. Insertion i
nduced coating wear was shown to impact the release triggered drug diffusion for both HA coatings loaded by adsorption as well as co-precipitated s
amples. Nevertheless, both drug eluting samples types fulfilled, even in the
presence of coating wear, the drug delivery criterion comprising a large initial release of antibiotics to eliminate bacteria infiltrating during surgery, fo
llowed by a controlled release with concentrations over the MIC of S. au- r
eus. The smooth coating topography and low coating thickness of biomi- m
etically deposited coatings in contrast to thick and rough plasma sprayed co
atings is expected to provide implant surfaces with superior insertion c
haracteristics and improved adhesive strength [93,94].
Prevention by Physical Modification
As microbial adherence is an vital pace in the pathogenesis of FBRI, i

nhibition of adherence appears to be a extremely appealing way for pr
evention. All vital steps in the pathogenesis, such as adhesion, accumu
lation and biofilm formation, re- present probable targets opposing tha
t prevention strategies could be managed (table VII). Even though ther
e is nowadays a extra methodical vision into the molecular pathogen
esis of device-related infection, as out- lined in serving 2, this has not
yet managed to strategies managed opposing specific adherence mech
anisms
P a g e | 90
especially because it is yet unfamiliar if a specific adhesin (e.g. protei

n, polysaccharide) is genus- or species-specific or merely strain-speci
fic. There fore, most of the presently industrialized strategies have co
ncentrated on the modification of health mechanisms, exceptionally o
f catheters. Alteration of the physical external (e.g. of a poly meric ca
theter) leads to a change in specific and nonspecific contact alongside
micro-organisms. Such a external modification of polymeric health
mechanisms could lead to a decreased microbial adherence via modifi
ed contact alongside proteins and platelets. The progress of so-called a
ntimicrobial polymers is aimed predominantly at the prevention of mi
crobial colonisation rather than microbial adherence. Mechanisms en
compassing antibacterials, disinfec- tants or metals have been assesse
d experimentally or in clinical examinations and are, in portion, comm
ercially obtainable and by now utilized in clinical requests, for examp
le intravascular catheters. Obliteration of
the biofilm embedding surface-adherent micro-or ganisms by enzyme
s or ultrasound plus consecutive antibacterial therapy as well as the m
echanical en hancement of antibacterial penetration across bio films
[163,195-197] are all curative strategies rather than preventive meas
P a g e | 91
ures. Therefore, it seems seeming that, because of the particular path

ogenesis of FBRI, ways that are managed opposing bacterial colonisat
ion of a mechanism are extremely promising. Health mechanisms ma
de out of a physical that should be antiadhesive or at least colonisation
-resistant in vivo should be the most suitable candidates to circumvent
colonisation and consecutive infection. In the last 1520 years there h
ave been a colossal number of studies dealing alongside this setback, i
n portion employing disparate strategies. A finished overview is given
in table VIII; most of the studies have been gave alongside intravascul
ar catheters because of their extensive use. Thus, the main focus of thi
s serving is on the discussion of adjusted catheter materials.
Development of Antiadhesive Polymer Materials by Physico-Chemica

l Modification
The most appealing way to obviate FBRIs should be to develop a heal
th physical that proves to be resistant opposing microbial adherence,
P a g e | 92
even afterward insertion into the bloodstream and even though the ev
er-occurring contact of the mechanism external alongside host factors
such as proteins and cells. There is facts that the intrinsic properties o
f a physical could be of supremacy considering confrontation to infection. Thus, enhancement of the external sense, tailoring the protein a
dsorption characteristics and im- clarifying the antithrombogenicity of
a given physical should be key factors in the progress of innovative,
infection-resistant materials. Though, this aim has not yet been graspe
d satisfactorily. Countless scutiny clusters have endeavored to develo
p polymers alongside new external properties that should lead to a re
duction of bacterial adhesion. Bridgett et al. [198] learned the adhere
nce of three isolates of S. epidermidis to polystyrene surfaces that we
re adjusted alongside a copolymer of poly(ethylene oxide) and poly
(propylene oxide). In vitro, a comprehensive reduction in bacterial a
dhesion was attained alongside all surfactants tested. Comparable afte
rmath were discovered by
Desai et al., who investigated the adhesion of S. epidermidis, S. aure
us and P. aeruginosa to
polymers that were surface-modified alongside poly(ethylene oxide).
They noted reductions in adherent bacteria of amid 70% and 95% cont
rasted alongside the untreated polymer. A photochemical coating of p
olymers was utilized by Dunkirk et al., [200] clarifying that the coati
ng decreased adhesion of a collection of bacterial strains. Tebbs et al.
[201] contrasted the adherence of five S. epidermidis strains to a poly
urethane catheter and to a business hydrophilic, coated polyurethane c
atheter (Hydrocath ). Adhesion of three strains to the coated catheters
was considerably reduced. Bacterial colonisation was more decreased
by the supplement of benzalkonium chloride to a hydrophilic polyuret
P a g e | 93
hane catheter (Hydrocath
Our own ways to develop anti
-infective materials encompassed the modification of polymer surface

s by radiation or radiate discharge techniques. By way of radiation gra
fting managing to a decreased in vitro adhesion of S. epidermidis, 2-h
ydroxymethylmethacrylate was covalently link ed to a polyurethane s
urface. [203,204]
More present work on external modification of polymer materials to st
op bacterial adhesion in- volved the use of sulfonated poly(ethylene o
xide) as surfactant in a polyurethane [205] or the introduction of glyc
erophosphorylcholine as a shackle lengthener in polyurethane. [206]
Both ways lead to increased water uptake and to lower bacterial adhe
sion. An overview generally on experimental scutiny on the external
modification of polymers and on attaching macromolecules such as al
bumin to surfaces in or der to stop bacterial adherence can be discover
ed elsewhere. [207,208] So distant, the merely such adjusted polymer
utilized in clinical requests is a hydrophilic, polyvinylpyr- rolidone-co
ated catheter (Hydrocath ) established on polyurethane. Its moderatel
y low thrombogenicity and low in vitro bacterial adherence ought to a
dditionally be of benefit considering infection resistance; though, this
has not yet been clarified in a clinical trial. A main disadvantage of all
of the beforehand delineated ways, that target chiefly at the modificat
ion of the external properties of frank materials such as catheters or su
pplementary mechanisms, is the fact that for thermodynamic reason
s the conception of surfaces that display a zero adhesion is plausibl
y not feasible. In an experimental discover that investigated the conn
ection amid bacterial adhesion and the free external enthalpy of adhesi
on of a colossal number of contrarily adjusted polymers, we dem- onst
rated that it is impossible to develop a polymer external that displays a
P a g e | 94
n definite bacterial zero adherence in vitro. [209] In particular, adh

erence of S. epidermidis to a collection of polymers alongside different external properties, generated by way of the radiate discharge met
hod, was investigated. [209] We discovered that adhesion of the bacte
ria to the adjusted materials cut alongside rising negative free enthalp
y values. A precise minimum number of adherent S. epidermidis cell
s might be proved at positive free enthalpy benefits at that adhesion
ought to be thermodynamically impeded. Hence, it seems impossible t
o design an definite antiadhesive friend rial that retains its properties e
ven in the extra convoluted in vivo situation, in that the innate extern
al properties are masked by adsorption of bacterial and
host components.
Combination of Antimicrobial Agents in Health Mechanisms
The loading of health polymers alongside antimicrobial substances
whichever for curative or preventive intentions has a long tradition.
The best recognized anti-infective, polymeric drug transport systems
are the polymethylmethacrylate-gentamicin bone cement and the poly
methylmethacrylate- gentamicin beads (Septopal ) utilized for treatm
ent of bone and soft tissue infections. [210,211] Vascular pros- these
s made from Dacron
have been indulged alongside assorted antibac
terial agents to craft infection-resistant grafts but lacking routine clin
ical request to date. [212-214] In present years, catheters or portions
of the catheter arrangement have been coated alongside antimicrobial
drugs, and a little of these antimicrobial mechanisms are by now com
mercially available. The main principle of such mechanisms is that an
antimicrobial substance (e.g. an antibacterial, disinfectant or metal ion
) is
P a g e | 95
bound seemingly to a catheter whichever undeviatingly or by way of

a messenger or incorporated into the inside of the polymer. If such a
mechanism comes into link alongside an aqueous nature, discharge of
the drug into the adjacent vicinity occurs. The number of the antimicr
obial substance released is affected by the processing parameters, loa
ding dose, requested method, molecular size of the drug and the physi
co-chemical properties of the polymeric de vice. A elevated antimicro
bial compression is grasped (at least initially) in the extremely adjacen
t vicinity of the mechanism external, generally exceeding the MIC and
mini mum bactericidal compression of susceptible organisms.
Most such materials display a discharge outline according to first-orde
r kinetics, alongside an primarily elevated drug discharge and consec
utive exponential cut of the released drug; though, extra urbane drugrelease arrangements alongside described discharge kinetics have addi
tionally been developed.
As yet, it is unclear whether such a mechanism is capable of inhibition
of microbial adherence each se, or if its attention is extra managed op
posing colonisation; though, at least an elimination of by now adheren
t micro-organisms ought to be attained for the period that the antimicr
obial compound is released in the vital concentrations. Thus, such m
aterials are exceptionally suitable to stop, for ex ample, infection in sh
ort-term catheters, that originates from contamination across the inser
tion or from hub contamination. Antibacterials There are a colossal
number of studies on the bonding of antibacterials to biomaterials. S
olovskij et al. [215] coordinated polymers to that ampicillin and 6-a
minopenicillanic acid were covalently bonded and that inhibited the in
vitro development of S. aureus. Though, most studies have concentrat
ed on the incorpo ration or shallow coating of antimicrobials rather th
P a g e | 96
an on covalent bonding by chemical reaction. Sherertz et al. [216] util

ized a rabbit ideal to examine intravascular catheters coated alongside
countless antimicrobial substances (dicloxacillin, clindamycin, fusidi
c acid and chlorhexidine). The frequency of
catheter infections was considerably decreased compared alongside
the manipulation cluster after the dicloxacillin- coated catheter was us
ed. We have investigated the combination of flucloxacillin, clindamyc
in and ciprofloxacin into polyurethane polymers and clarified a substa
ntial reduction of the in vitro adherence of S. epidermidis. [204,217] I
n one more way, a commercially obtainable central venous, hydrophili
c-coated polyurethane catheter (Hydrocath) was loaded alongside the
glycopeptide teico planin. [218] In in vitro studies as well as in a mou
se ideal, the skill of this catheter to stop colonisation alongside S. epi
dermidis and S. aureus, re spectively, was proven for a era of at least
48 hours, rendering the catheter suitable to stop early-onset infection.
[218,219] To spread the anti microbial spectrum of such a catheter to
contain Gram-negative bacteria and fungi, a combination of teicopla
nin alongside silver was incorporated into Hydrocath catheters, that ex
hibited substantial ac tivity opposing S. epidermidis, E. coli and C. alb
i cans. [209]
Metals Amid metals alongside antimicrobial attention, silver has incre
ased the attention of countless investigators because of its good antimi
crobial deed and low toxicity. Silver has additionally extensively been
utilized for the progress of infection-resistant urinary catheters. Siosh
ansi [251] utilized ion implantation to deposit silver-based coatings o
n a silicone rubber, that thereafter clarified antimicrobial activity. Silver-copper external films, sputter-coated onto cathe- [250] ter materia
ls, additionally displayed antibacterial attention opposing P. aeruginos
P a g e | 97
a biofilm formation. [252] In a extra present piece of scutiny, an ion

beam tech nique requesting low implantation power has been utilized
for the formation of silver nano-particles on the external of polymers
that exhibited an enhanced ef fect on bacterial adhesion. [253] We in
dustrialized an antimicrobial polymer by attaching silver ions to acidadjusted, negatively charged polyurethane surface. [209]
Another way is loading of a hydro philic polyurethane catheter alongs
ide silver nitrate. In supplement, surface-coated polyurethane catheter
s [254] alongside a silver external thickness of 1520 A have been i
nvestigated alongside regards to their biocompatibility and antimicro
bial efficacy, displaying considerably cut adherence of Gram-positive
and -negative micro-organisms in vitro. [255] More attention has be
en increased considering mechanisms in that silver is distributed in for
m of nano-particles or in combination alongside supplementary agen
ts such as carbon and platinum. The Erlanger silver catheter uses a
microdis persed silver knowledge to rise the number of obtainable ion
ised silver. [256] The Oligon catheters are composed of polyuretha
ne in that carbon, silver and platinum particles are incorporated, that l
eads to an electrochemically driven discharge of silver ions in the bey
ond and inner vicinity of the catheter surface. Though, a peripherally
implanted central catheter established on this knowledge (Olimpic, V
ygon, Cirencester, UK) has been kept from the marketplace at least in
Germany because of mechani cal setbacks associated alongside this ki
nd of catheter. A extra present progress is the Oligon Vantex
cathet
er (Edwards Attendance Sciences, Irvine, CA, USA). [257] Suppleme

ntary ways are catheters alongside ac tive iontophoresis knowledge i
n that micro-organisms are repelled by mechanical present generate
d from a carbon-impregnated catheter [258] or whereas low-amperag
P a g e | 98
e present is produced by two mechanical ly charged parallel silver wir

es helically veiled concerning the proximal segment of silicone cathe t
ers. [259]
Several clinical studies have been gave alongside silver-containing int
ravascular catheters. In a randomised, prospective discover in haemat
o-oncological patients, a silver sulfate-polyurethane catheter (Frese
nius AG, Bad Homburg, Germany UK) was associated alongside a co
nsiderably lower rate of CRBI contrasted alongside the manipulation c
luster (10.2% vs 22.5%, p = 0.01). [260] In three examinations, the
Erlanger silver catheter in that the silver is microdispersed was eval
uated. [256,261,262] In the mature populace, a reduction in catheter
colonisation and in catheter- associated sepsis was observed; though
, the au- thors utilized criteria for ascertaining CRBI that differ ed fro
m most supplementary studies. A extra present clinical investigation f
loundered to display a statistically momentous difference in the colon
isation rate of the silver cathe ter contrasted alongside a manipulation
catheter. Ranucci et al. [257] contrasted the Oligon Vantex catheter,
com acted of silver, carbon and platinum alongside a benzalkonium c
hloride-treated catheter (Multi-Med, Edwards Attendance Sciences, Ir
vine, CA, USA) in a prospective randomised trial. Use of the Oligon
Vantex catheter cut the rate of catheter
colonisation by 11%,
as the rate for CRBI did not differ considerably amid the Oligon Vant
ex and manipulation groups.
Innovative Ways for the Prevention of Device-Related Infections

A extremely interesting way to stop biofilm formation as a prerequisit
e for CRI has been sug gested by Khoury et al. [196] They discovered
that by request of an external stimulus, for example an mechanical ea
P a g e | 99
rth jointly alongside antibacterials, the killing of biofilm-embedded ba

cteria is melodramatically en hanced (e.g. killing of P. aeruginosa by t
o bramycin). Even though it is extra of a curative strategy than a prev
entive compute, the use of an mechanical present could be functional
for the prevention of CRI, as was beforehand pointed out. Related approaches aimed at eradication of biofilms contain the joined use of ult
rasound jointly alongside antibacterials [163,197] and, perhaps, the
bactericidal ef fect of extracorporeal surprise waves on S. aureus. One
more way to craft anti-infective surfaces has been industrialized on t
he basis of so-called intelligent polymers. Because a disadvantage of
the presently obtainable antimicrobial catheters is the constant leachi
ng out of alert substances after the mechanism is in link alongside blo
od (or supplementary body fluids), a arrangement was industrialized i
n that an anti microbial compound is released on demand. This might
be attained by attaching iron to a chemically adjusted polymer surface
; next in a subsequent pace, a fluoroquinolone was coupled. In vitro e
xaminations alongside P. aeruginosa clarified freedom of the antibacte
rial merely in the attendance of the bacteria. [276] [277].
Conclusion
More than prevention of such implant based devices, I think we can e
xpect to see more approaches, that target the management of such pro
blems, by using design based solutions. Prevention rather than cure, w
as the paradigm followed earlier. However, clever mechanical designs
can offer more innovative ways to tackle biofilm management, which
is the core of the implant related disease problem.
P a g e | 100
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EXECUTIVE SUMMARY

The application of medical devices either for temporary or permanent us

Materials for Biomedical Applications.

Modalities for Analysis

Atomic Force Microscope.

X-ray photoelectron spectroscopy..

Attenuated total reflection Fourier transform infrared spectr

Attachment of Microbe on Device Surface

Management of Medical Device Associated Infections :

Salvage of Device and Treatment with Antimicrobial Agents

The rate of implant surgery is steadily increasing. Each implantation is a

Materials for Biomedical Applications

Biomaterials, utilized to reinstate a broken construction and purpose in t

H)2, is the most usually utilized bioactive ceramic physical in clinical ap

drophilic polymers or imaging in a fluid nature t in non-contact mode is

TEM and AFM pictures suitably y of the alike polyamide e polymeric c

X-ray photon spectroscopy (XPS).

Secondary ion mass spectrometry (SIMS).

Attenuated total reflection Fourier transform infrared spectroscop

Auger electron spectroscopy (AES). Auger electron spectrosco

X-ray photoelectron spectroscopy. Scan photoelectron spectros

XPS abilities could precisely have an adverse result on the XPS a

Figure 5a. Survey (low resolution) XPS scans of a polyurethane (PU) su

Figure 5b. High resolution XPS C1s detailed spectra of a polyur

Resolution XPS Spectra clearly indicating that the surface has be

in order to minimize collection period, and probable damage to a

variation as a purpose of example depth can be obtained by meas

Secondary ion mass spectrometry (SIMS) and time-of-flight s

ed ion beams. Amid two consecutive pulses, all of the secondary

rating link slant and XPS measurements and complementing data

Infrared spectroscopy (IR) and attenuated finished reflection

Attachment of Microbe on Mechanism Surface

Microbial adherence to external bodies depends on the cell extern

c receptors for colonising micro-organisms. [34-36] In the vascu

The S. epidermidis autolysin AtlE that mediates main attachment

Cell Proliferation & Intercellular adhesion

tained from blood of patients alongside FBRI, a forceful associat

Intercellular signalling, frequently denoted to as quorum detectin

Management of Health Device Associated Infections :

Whenever an infection of an indwelling or im planted external bo

hanism, antimicrobial therapy and on supplementary procedures t

Salvage of Mechanism and Treatment alongside Antimicrobi

nimum inhibitory concentra- tion [MIC] for at least 72 hours) of

expert opinion rather than on the aftermath of appropriate clinical

Lilja, M., Welch K., strand M., Engqvist H., Strmme

Lilja, M., Forsgren, J., Welch K., strand M., Engqvist

Lilja M., Lindahl C., Xia W., Engqvist H., Strmme M.

c from Hy- droxyapatite Coatings. J Biomater Nanobiotech

Lilja M., Srensen J.H., Brohede U., strand M., Procte

Srensen J.H., Lilja M., Srensen T., strand M., Procte

Srensen J.H.*, Lilja M.*, Srensen T., strand M., Procte

Materials and Methods

Figure 3. Overview of the studies presented in t

Materials and Methods

the bactericidal effects of TiO2 photocatalysis of anatase phase do

Figure 4. Overview of samples used in Paper I

UV Treatment and Photocatalytic Activity Testing

Bacterial Viability Analysis

Resazurin was employed as an indicator to evaluate the viability

of the cells were analyzed after 3 days of culture by Calcein AM staini

Antibiotic Loading Procedures

In Paper VI and VII, Tobramycin was loaded into HA coated sample

Biomechanical Insertion Tests

The biomechanical properties of HA-B coatings deposited on TiO2 c

Srensen J.H., Lilja M., Srensen T., strand M., Procte