Surface Enginnering on Medical Devices.

Surface Engineering
on
Medical Devices.
Caxias do Sul
17/04/2014

©. Property of TECNALIA.
Surface Engineering on Medical
Devices.
Problems and challenges addressed
with Surface Engineering techniques
from the research, development,
evaluation and validation points of view.

Surface Engineering on Medical Devices. Abstract
Medical Devices play an increasingly important role in clinical treatments. From surgical
tools to permanent implants, they are both the key of a successful treatment and often the
source of adverse reactions. Success or failure most of the times will depend on events
occurring on the medical device – human tissue interface, which typically are heavily
influenced by the biomaterial surface properties. Therefore, surface treatment and coating
technologies constitute powerful tools in the development of new devices and improvement
of the performance of existing ones.
We will review a number of surface technologies that are applied on medical devices, as
well as a number of case studies where issues such as infection resistance or tissue
integration of medical devices are address through the development of new surfaces.
Surface Engineering on Medical Devices.

Index
-. Tecnalia.
-. Surface engineering vs. biomedical RTD.
Problems & challenges.
Regulatory aspects.
Economic aspects.
Intellectual property rights.
Case studies.
i) Antimicrobial surfaces.
ii) Tissue integration/regeneration.

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Medical Devices: “…any instrument, apparatus, appliance, software, material or other
article, … to be used specifically for diagnostic and/or therapeutic purposes…”
Implant: “… Any device which is intended
— to be totally introduced into the human body or,
— to replace an epithelial surface or the surface of the eye,
by surgical intervention which is intended to remain in place after the procedure.
Transient: < 60 minutes.
Short term: < 30 days.
Long term: > 30 days.
Properties: mechanical, biocompatible,…
Challenges: tissue interaction & integration,
infections, …
how to make them more safe,
durable and efficient
Solution strategies: novel surfaces & biomaterials.

With modern protocols, the incidence of infections associated to placement of implants
has become very low: e.g. estimated in 0.5–5% for total joint replacements.
Nevertheless, infections still cause a huge impact in terms of morbidity, mortality, and
medical costs. e.g. in orthopedics, the treatment of each single episode of infected
arthroplasty costs >$50,000.
Aprox. half of the nosocomial infections are related to the use of medical devices.
The pathogenesis of peri-implant infections. -> the critical dose of contaminating
microorganisms to produce infection is much lower with a foreign material at the surgical
site. Key: cell anchorage and fixation and formation of an adherent biofilms.
As in other medical fields, prevention represents a main goal, which relies on a series of
strategies on different ground levels:
-. in the past decades, control of environmental and personnel contamination has been
a principal target to cut down the rate of nosocomial and post-surgical infections.
-. the establishment of effective protocols of peri-operative antibiotic prophylaxis.
Infections vs. antimicrobial surfaces.

-. The interface biomaterial surface-surrounding tissue is where accidental
contamination can first develop into colonization and, subsequently, into the establishment
of a clinically relevant infection. -> the most convenient way to interfere with the early
phases of microbial adhesion is a modification of the chemistry or the micro/nanotopology of
the out-layer of the device.
Locally applied antibiotics under temporally controlled release present many advantages
over systemic clinical treatments, e.g. efficiency and side effects. Biofilm formation at the
implant tissue interface, a barrier that diminishes or disables the penetration of systemic
antibiotics. This can be achieved by a coating on top of the medical device.
 Bacteriostatic and antimicrobial* surfaces: ion implantation of Ag / Si.
 Drug release: ciprofloxacin.
 Drug attachment: vancomicyn.
*: bacteriostatic: inhibiting growth or multiplication of bacteria.
antimicrobial: killing microorganisms or suppressing their multiplication or growth.
Antimicrobial surfaces.
Infections vs. antimicrobial surfaces.

Bone ?
-. Bio-nanocomposite made up of an organic fiber matrix (collagen,…) stiffened by ceramic
nano-crystals
(30-50nm length; 15-30nm width, 2-10nm thickness… Mj.J.Olszta et al.)
-. Non homogeneous structure.
-. Dynamic material,
that can remodel and
adapt to the
bio-mechanical
environment.
http://training.seer.cancer.gov
Tissue integration / regeneration vs. osseoinductive surfaces

Human bone AFM
. .

Human bone AFM
. .
Bone particle sizes:
10-30nm

Implants & prostheses:
-. Often Ti & alloys: relatively light & good mechanical prop.
-. Natural oxide layer (1.5 – 10 nm thick)
-. Tissue regeneration around titanium, i.e. osseo-integration,
“…a direct connection between living bone and a load-carrying endosseous implant at light
microscopic level…” .
Osseo integration depends on
-. Implant material
-. Implant design
-. Status of bone
-. Surgical technique
-. Implant loading conditions
-. Surface quality

.
Osseo integration depends on: Surface quality
-. Surface chemistry.
HAp, bioactive ceramics,…
Ti, Ta, ... oxide layer
Ion release
Corrosion resistance
bioactive molecules
-. Surface physical properties:
visco-elasticity,
surface energy,…
-. Surface topography.
Milimiter roughness
Micrometer “
Nanometer “

Regulatory aspects
… rules relating to the safety and performance of medical devices were harmonized
in the EU in the 1990s. The core legal framework consists of 3 directives:
• Directive 90/385/EEC regarding active implantable medical devices,
(devices that require external power sources in order to function properly)
• Directive 98/79/EEC regarding in vitro diagnostic medical devices.
(devices used for the examination of specimens taken from the human body)
• Directive 93/42/EEC regarding medical devices
and,
… requirements and procedures for the marketing authorization for medicinal products for
human use, as well as the rules for the constant supervision of products after they have
been authorized, primarily laid down in:
• Directive 2001/83/EC relating to medicinal products for human use.
Regulatory aspects.

Regulatory aspects
Some key issues:
• Identify Directives and Regulations: Is it really a medical device according to Directive
93/42/EEC?
“…any instrument, apparatus, appliance, software, material or other article, … to be used
specifically for diagnostic and/or therapeutic purposes…”
• Classify according to MDD Annex IX:
• How to “build” the Technical File demonstrating compliance?
• Enough to “convince” the Notified Body?
• How long and cost of achieving the CE marking?
Regulatory aspects.

Regulatory aspects
Some key issues:
1. Description of product family and justification for why your device falls into that family
2. Device intended use
3. Description of device components, specifications, packaging and literature
4. Device manufacturing Process
5. List of accessories to your device
6. Location of design responsibility and manufacturing facilities
7. Classification along with rationale for classification
8. Chosen compliance route according to applicable Directive(s)
9. Declaration of Conformity stating manufacturer’s compliance with applicable Directive(s)
10. Shelf life and environmental limitations of device
11. Retention of quality assurance, Competent Authority and Notified Body records
12. Vigilance reporting and Medical Device Reporting procedures
13. How and when to contact Competent Authorities
14. Name of and contract with your Authorized Representative
15. Subcontractor names and addresses if applicable
16. Essential Requirements
17. Design input specifications
18. Application and references to Standards and Guidelines
19. Testing results and clinical evaluations
20. Risk analysis
21. Instructions for Use and Labeling
Regulatory aspects.

Regulatory aspects
Some key issues:
Testing program?
= RTD testing?
Harmonized standards?
Quality System in compliance with ISO 13485?
Regulatory aspects.

Economic aspects
Some key issues:
• Medical Devices where the technology could be implemented?
• Public or private health services?
• Performance improving technology?
• Cost saving technology?
• Regulatory process time and cost?
• Scaling up of technology vs. ISO 13485?
Economic aspects.
Some key issues:
• Freedom to operate?
• Effective protection?
• Time to market vs. patent life?

Index
-. Tecnalia.
Regulatory aspects.
Economic aspects.
Case studies.
Ion implantation
Antibiotic release
Plasma+click attachment

M&M: Substrate: AISI 316 LVM
Si+ ion implantation.
Ref: Si-I: 5×1016 ions/cm2, 50keV, angles of ion incidence of 90º.
Ref: Si-II: 2.5×1016 ions/cm2, 50keV, angles of ion incidence of 45º.
Properties/results:
Bacteriostatic surfaces. ion implantation of Si.

Bacteriostatic surfaces:
ion implantation of Si.
Biocompatibility:
Bacteria adhesion rates in a parallel plate flow chamber microorganisms were let to adhere
under dynamic (flowing the bacterial suspension) and static conditions (stopping the flow).
for the dynamic (jo) and static (n) (↓↑:statistical significance, p <0.05).
[S. aureus ATCC29213, S. epidermidis ATCC35984 (S. epidermidis4) and S. epidermidis HAM892 (S. epidermidis2)].
Bacteriostatic surfaces.
[Applied Surface Science, In Press, Accepted Manuscript, Available online 4 April 2014]

Drug released: ciprofloxacin
M&M process parameters
Precursor: N,O-bis-tert-butyldimethylsilylated ciprofloxacin (silylciprofloxacin),
+ the low-energy plasma activation of the silylated groups
Ar or N2 RF plasma to surfaces coated with chemically modified ciprofloxacin.
+ hydrolytic profile of silyl carboxylates in aqueous media/ physiological media.
+ residual tert-butyldimethylsilanol by product arising from the hydrolysis is nontoxic.
Antimicrobial surfaces. Plasma Polymerized Silylated Ciprofloxacin

Tests / results.

Tests / results.
 An antibiotic, ciprofloxacin, has been disilylated and successfully incorporated into a
coating by a plasma polymerization process, keeping its antibiotic activity once released
by hydrolysis in physiological conditions.
 The release dynamics are significantly influenced by the plasma processing parameters.
 The plasma polymerization technique, in combination with suitably silylated prodrugs,
offers the possibility of tailoring the coating properties, e.g., thickness and degree of
polymerization, and thus the release dynamics of the antibiotic, to a wide range of
medical devices and clinical contexts.
Plasma Polymerized Silylated Ciprofloxacin as an Antibiotic Coating.
Plasma Proc. and Polymers 8 (7) (2011) 599–606.

Index
-. Tecnalia.
Regulatory aspects.
Economic aspects.
Case studies.
Ion implantation
Antibiotic release
Plasma + click attachment

Prof of concept:
A) Plasma polymerization.
B) Vancomycin modification with azide linker.
C) “Click” chemistry.
D) Evaluation of antibiotic activity, against Staphylococcus epidermidis
Antimicrobial surfaces. A “Plasma-Click” Dual Procedure

M&M:
A) Plasma surface modification.
Substrate material: glass slides / KBr.
Technique: Ion Gun Inverse Magnetron (IGIM).
Optimization of plasma polymerization process.
Precursor Acrylic Acid.
Objective: COOH functional groups at the surface.
Process parameters:
Pressure Ar Flow
Acrylic
Acid Flow
C
O
2 Time Distance Current Voltage
[mbar] [µL•min-1
] [g/h]
[
µ [min] [mm] [A] [V]
CO2H-0 E-3 70 3 - 30 117 0,07-0,08 340
CO2H-1 E-3 70 1 - 30 117 0,07-0,08 340
CO2H-2 E-3 70 1 - 30 117 0,25 340
Ref.
Process Conditions

~1706 cm-1 C=O
~ 2900–3300 cm-1
OH
C-O 1280 cm-1
~1706 cm-1 C=O
C-H 1450 cm-1
1640 cm-1 C=C
M&M:
Characterization: FTIR.
Ref.
CO2H-1
CO2H-2
CO2H-0

Ion implantation and plasma based processes on Medical Devices Antimicrobial surfaces.
M&M:
Optimization processes with constant current of 0.07-0.08 A and 30 minutes.
Characterization: density of COOH groups by colorimetry with toluidine blue.
Results
Pressure Ar Flow
Acrylic
Acid Flow CO2 Flow Time Distance Current Voltage Colorimetry
[mbar] [µL•min-1
] [g/h] [µL•min-1
] [min] [mm] [A] [V] [nmol•cm-2
]
CO2H-3 E-3 70 3 - 30 117 0,07-0,08 340 0,46 (±0,01)
CO2H-6 E-3 - 3 132 30 117 0,07-0,08 337 0.99 (±0.09)
CO2H-7 E-3 - 3 70 30 117 0,07-0,08 337 0.35 (±0.16)
CO2H-9 E-3 - 3 265 30 117 0,07-0,08 337 1.44 (±0.38)
CO2H-11 E-3 - 1,5 132 30 117 0,07-0,08 337 1.87 (±0.22)
Ref.
Process Conditions
Selected process parameters:
Acrylic Acid Flow 1.5 µL min-1; CO2 gas flow 132 µL min-1; t= 30 minutes;
current 0.07 to 0.08A, voltage 337V.
Density of COOH groups: 1.87±0.22 nmol/cm2.

M&M:
Vancomycin hydrochloride in DMSO
+ DMF and 4-methylazido-benzylamine,
… mixture cooled to 0ºC
…+ HBTU in DMF and DMSO
…+ DIPEA.
… stirred overnight at room temperature.
… quenched by adding it dropwise to acetone,
precipitated, filtered, and washed.
… modified vancomycin purified by RP-HPLC.
.

M&M:
Purification by RP-HPLC.
Characterization: FTIR, MS Spectrometry.
FTIR: Vancomycin and vancomycin azide in KBr, N3 at ~2100 cm-1
Reversed phase HPLC chromatograms:
Eluent MeCN/H2O/TFA; retention time [min.]
Vancomycin, top-right
and vancomycin azide, below-right.

M&M:
C) “Click” chemistry.
Method: surface amidation with propargylamine of plasma modified surface
“click” chemistry with vancomycin-azide.6
Van- azide in PBS + alkyne glass slide + … addition of CuSO4 solution and sodium
acorbate solution, under nitrogen at room temperature for 24 h, washed with PBS.
Characterization: XPS after (ultrasound in distilled water).
The N signal corresponds to the N atom in the propargylamine, C3H5N
The Cl signal corresponds to the Cl atom in the original vancomycin molecule = C66H75Cl2N9O24
Ref. Peak BE At.% Ref. Peak BE At.%
Control C1s 285.06 70.7% "click"ed C1s 288.79 75.4%
O1s 536.53 26.7% vancomycin O1s 536.33 18.8%
N1s 404.48 2.6% N1s 404.1 5.4%
Cl2p3 0 0.0% Cl2p3 204.72 1.0%

M&M:
D) Evaluation of antibiotic activity: immersion test.
Against Staphylococcus epidermidis (CECT 231) bacteria
Surface modification prepared on inert glass; control: untreated glass.
i) immersion glass samples, at different bacterial concentrations:
5.9E+01, 1.2E+02 and 1.2E+03 c.f.u./mL, in nutrient broth, cultured at 37ºC
and counting bacterial viability after 18 hours. n= 2 or 3 per concentration.
Initial bacterial Inhibition
concentration at 18h
c.f.u. / ml % S.D.
5.9 x10 99.85% (±1.4)
1.2 x 102
96.33% (±2.4)
1.2 x 103
95.80% (±4.9)

M&M:
D) Evaluation of antibiotic activity: direct contact.
Against Staphylococcus epidermidis (CECT 231) bacteria
Surface modification prepared on inert glass; control: untreated glass.
ii) following indications of the JISZ 2801 standard; culture at 37ºC and 100% humidity;
extraction and counting after 10, 24 and 48 hours. n= 3 per test time.
Initial bacterial Inhibition Inhibition Inhibition
concentration at 10 h at 24 h at 48h
c.f.u. / ml % % %
4 x 105 96.4%
(±2.4)
87.4%
(±8.1)
87.8%
(±7.1)

Conclusions: A “plasma-click” based coating has shown to be an effective technique for
producing surfaces with antibiotic activity.
 The “click”ed antibiotic, i.e. vancomycin, showed antibiotic activity against
Staphylococcus epidermidis after all the coating processes (e.g. azidation of the
vancomycin and click chemistry).
 The plasma polymerization technique allows controlling the concentration of CO2H on
the surface of the coated material, that would affect the final max. concentration of
vancomycin, and consequently the antibiotic activity.
 The strategy described is feasible and could be used for several antibiotics.
Furthermore, such antibiotic coatings can be deposited on any medical device that can
withstand the plasma process.
 Further work is necessary to determine the optimum vancomycin concentration at
the surface and confirm the antibiotic activity against other bacteria, e.g.
Escherichia coli, Staphylococcus aureus, Pseudomona aeruginosa,…
“Plasma-Click” Based Strategy for Obtaining Antibacterial Surfaces on Implants.
Plasma Proc. Polymers 10(4)(2013)328–335

Index
-. Tecnalia.
Regulatory aspects.
Economic aspects.
Case studies.
Ion Implantation

Tissue integration
Tissue integration.
CO ion implanted implantable musculoeskeletal implants.
..

AFM
surface
topography
Ref. E
Ref. A Ref.B
Ref. C Ref. D
Ref. E
Ref. A Ref.B
Tissue integration

In vitro cell culture tests:
-. Cell attachment.
-. Cell proliferation [Surf. Coat Tech vol. 196 (2005) p. 321-326]
-. Cell morphology.
-. Cell apoptosis. [Surf. Coat Tech vol. 201 (2007) p. 8091-8098]
-. ALP activity.
Tissue integration

In vitro culture tests
Cell attachment.
 16 samples of each i.i. & ctrol Ti discs,
 Sterilized by UV light
 placed individually into 6-well plate,
 Inoculated with 1.5 x 105 human bone-cells
 Incubated for 4h at 35 ºC, 5% CO2.
 After rinsing and fixing
Image Analysis System used to quantify
nº attached cells.
Cell Attachment
0
400
800
1200
1600
2000
2400
2800
C A B
Sample ref.
Numberofcells/cm2
)
Cell Attachment
0
400
800
1200
1600
2000
2400
2800
E D
Sample ref.
Numberofcells/
cm2
C & E control
Tissue integration

Cell proliferation.
 Seeded at conc. of 2,5 e4 cell/well
 placed individually into 6 well plates.
 Incubated for 24, 48, 144 & 192 hours
at 35 ºC and 5% CO2.
 Cells washed and collected by
trypsinisation with 0.25% trypsin-EDTA
solution (SIGMA).
 Cells were stained with 7-Amino-
Actinomycin D (7 AAD) (BECKTON &
DICKINSON)
 Cells quantified by flow cytometry
Cell Proliferation
-1
1
3
5
24 48 144 192
Incubated time (hours)
GrowthRatio
ControlTi Treated Ti
*
Tissue integration

ESEM
AFM
Cell morphology.
Tissue integration

Cell apoptosis.
 Seeded at a conc. of 6 x 105 cell/well
 placed individually into 12 well plates.
 Cells incubated for 24 and 72 h. at 35ºC and 5%CO2.
 Cells were washed and collected by trypsinisation with 0.25% trypsin-EDTA solution.
 Cells lysed and their apoptosis state was tested using a flow cytometry Kit, which detects
the concentrations of PARP, Bcl-2 and Caspase-3 molecules.
24 hours 72 hours
Tissue integration

Alkaline Phosphatase
0
0,5
1
1,5
2
2,5
3 days 8 days 16 days
RelativeALPactivity
Ion implanted
Control Ti
sample
Expression of Alkaline Phosphatase
The activity of the alkaline phosphatase enzyme was determined measuring the
final fluorescence emitted as a result of an enzyme based reaction (4-MUP). The
use of a positive control confirms that the assay conditions are accurate.
Tissue integration

In vitro cell culture tests. Conclusions:
• Results depend on the treatment parameters.
• Osteoblast growth is favoured.
• Cell morphology indicates a better cell behaviour.
• Lower apoptosis signal.
• Higher ALP activity
Tissue integration

In vivo tests on dental implants.
What’s a dental implant?
Typically a Ti/Ti alloy screw replacing
the tooth root and supporting a new
artificial tooth.
Requirements
It must transmit the masticating forces
to the jaw bone,
i.e. a good osseointegration is
mandatory.
Tissue integration

How does it work ?
1. Insertion of the implant into the bone.
2. Integration on the surrounding bone (3-8 months).
3. Abutment connection.
4. Fixation of the crown
From Periodontal
Associates
Tissue integration

Treatment example.
From www.oral-implants.com
Tissue integration

Osseointegration (%)
30%
40%
50%
60%
70%
80%
90%
on Ti6Al4V on CPTi
Lifenova
Untreated
Osseointegration tests
on the tibial plateau of NZW rabbits.
as machined vs. ion implanted
two base materials
Results:
Significant differences on poor
bone density areas.
Ion impl.ed
Untreated
Tissue integration

i) Test procedure & ethical committee (Univ. Barcelona)
ii) 12 implants x 6 different surfaces.
iii) 6 implants x 6 surfaces at month 3.
6 implants x 6 surfaces at month 6.
P2I P3I P4I P2D P3D P4D
B 1 A B C D E F
B 2 F A B C D E
B 3 E F A B C D
B 4 D E F A B C
B 5 C D E F A B
B 6 B C D E F A
B 7 A B C D E F
B 8 F A B C D E
B 9 E F A B C D
B 10 D E F A B C
B 11 C D E F A B
B 12 B C D E F A
Tests in jawbone.
Case study: in vivo tests

BIC %, ESEM evaluation.
0%
10%
20%
30%
40%
50%
60%
70%
80%
Ion implantation Control Commercial
average
BIC
3 months
6 months
ESEM evaluation.
Case study: in vivo tests
Control vs. Ion Implantation
* *

BIC %, histological evaluation.
0%
10%
20%
30%
40%
50%
60%
70%
80%
Ion implantation Control Commercial
average
BIC
3 months
6 months
Histological evaluation.
Control vs. Ion Implantation
[International Journal of Oral and Maxillofacial Surgery, 37(5),(2008), 441-447]
* *
Tissue integration

ESEM-EDS.
Tissue integration

ESEM-EDS.
Implant
Mature
bone
New
bone
[International Journal of Oral and Maxillofacial Surgery, 38(3), (2009), 274-278]
Tissue integration

BIC %
0
10
20
30
40
50
60
70
0 Month 1 Month 3 Month 6
Ion implanted Commercial Average Control
Tissue integration

N patients: 19
N of mini-implants: 22
Inclusion criteria:
Healthy patients from both sexes, undergoing treatment
with conventional commercial implants, with type III or IV
bone quality (as defined by Lekhölm y Zdart)
Exclusion criteria
Minors, pregnant women, local or systemic contraindications
Clinical trial 277/06/EC
Tissue integration

Participating Clinics
Pr. Dr. C Gay Escoda. University of Barcelona, Faculty of Odontology.
Dr. M de Maeztu. Private practice. Tolosa, Spain.
Approval and authorization
Ethical committees of the University of Barcelona and Hospital Donostia.
AGEMPS (Spanish Agency for Drugs and Medical Devices).
Tissue integration

1.8 mm diameter
5 mm long
Tissue integration

Surgery: drilling.
Tissue integration

Surgery: implant insertion.
Tissue integration

Surgery: implant extraction.
Tissue integration

Histomorphometric study.
Tissue integration

Histomorphometric study.
3.8
4.8
3.8 56% 18% 66% 87%
4.8 28% 56% 71% 75%
3.8 75% 81% 54% 92%
4.8 70% 81% 66% 83%
3,8 41% 83% 99% 88%
3.8 64% 63% 87% 90%
4.8 17% 36% 40% 67%
3.8 58% 71% 94% 96%
4.8 49% 69% 62% 89%
servacione
s
%BIC Ctrl
s/ESEM
%BIC I.I.
s/ESEM
%BIC Ctrl
s/histología
%BIC I.I.
s/histología
dia 46,2% 54,8% 57,9% 62,9%
viación std 21% 23% 21% 25%
%BIC Histology
30,0%
40,0%
50,0%
60,0%
70,0%
80,0%
90,0%
% BIC Ctrl % BIC I.I.
Conclusions:
-. No negative reaction.
-. Larger osseointegration.
Tissue integration
[International Journal of Oral and Maxillofacial Surgery, 42(7) (2013) 891-896]

Human bone on implant surface AFM
. .
Tissue integration

Conclusions:
-. Higher osseointegration on poor bone density areas.
-. Faster osseointegration than untreated implants.
-. Higher osseointegration than in the case of implants with
commercial surfaces, i.e. micro-roughened TiO2.
-. Ion implanted surfaces show new bone formation arising
from the implant, unlike control samples.
Higher and faster levels of osseointegration
=
Shorter patient treatment times & treatments available for
cases/patients with lower bone quality.
Tissue integration

Tissue integration
Tissue integration.
Neutral (Ne,Ar,Xe,Kr) ion implantation vs. cells.

Tissue integration.
TiGr4, 1Ne40
TiGr4, 1Ne80
TiGr4, 2Ne40
TiGr4, polished
M&M:
Ion implantation of Ne.
1×1017 and 2×1017 ions/cm2,
40keV and 80keV.
Tissue integration

M&M:
Ion implantation of Ar.
1×1017 and 2×1017 ions/cm2,
40keV and 80keV.
Tissue integration.
TiGr4, 1Ar40
TiGr4, 1Ar80
TiGr4, 2Ar40
TiGr4, polished
Tissue integration

M&M:
Ion implantation of Kr.
1×1017 and 2×1017 ions/cm2,
40keV and 80keV.
Tissue integration.
TiGr4, 1Kr40
TiGr4, 1Kr80
TiGr4, 2Kr40
TiGr4, polished
Tissue integration

Ion implantation and plasma based processes on Medical Devices
M&M:
Ion implantation of Xe.
1×1017 and 2×1017 ions/cm2,
40keV and 80keV.
Tissue integration.
TiGr4, 1Xe40
TiGr4, 1Xe80
TiGr4, 2Xe40
TiGr4, polished
Tissue integration / regeneration.

.
TiGr4, 1Xe80
TiGr4, 1Xe40
TiGr4, 2Xe40
TiGr4, 1Ar80
TiGr4, 1Ar 40
TiGr4, 2Ar 40
TiGr4, 1Ne80
TiGr4, 1Ne40
TiGr4, 2Ne40
TiGr4, polished
TiGr4, 1Kr80
TiGr4, 1Kr40
TiGr4, 2Kr40
Tissue integration

Tests / results:
Wettability and roughness:
Tissue integration.
75
77
79
81
83
85
87
89
91
93
95
0 1 2 3 4 5 6 7 8
Ra (nm)
Contactangle(º)
Ne Ar Kr Xe Control
Ref. Ra
Peak to
peak
distances
Contact
angle
(nm) (nm) (º)
Control 0.295 N.A. 82.6±5.2
1Ne80 0.56 119±5 78.6±1.6
1Ne40 0.61 67±2 85.1±2.2
2Ne40 1.49 91±2 88.2±0.9*
1Ar40 2.15 82±3 81.0±0.5
2Ar40 2.21 160±4 84.0±2.4
1Ar80 2.68 122±4 83.1±1.0
1Kr80 2.6 98±3 85.5±2.4
1Kr40 1.48 89±3 87.0±0.9
2Kr40 1.55 132±2 87.2±3.2
1Xe80 2.47 162±4 86.9±2.5
1Xe40 3.57 185±3 86.9±1.0
2Xe40 7.27 217±4 88.8±2.1*
Tissue integration

Tests / results:
Cell culture and adhesion
hFOB 1.19 (cultured in accordance with ATCC).
1.5 x 104 cells were seeded onto the 8 mm diameter Ti discs, and incubated for 4h and 24 h
(n=3). Besides, cells were also plated on untreated Ti-discs (n=5) as a control.
Cell adhesion was assessed using the 4-[3-(4-Iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-
1,3-benzene disulfonate (WST-1) assay.
Tissue integration.

Tests / results:
 The contact angle measurements: most of the treated surfaces became more
hydrophobic, as compared to the control sample, although the change was small, i.e. it
was only statistically significant for the samples 2Ne40 and 2Xe40.
 The contact angle varied most for titanium samples ion implanted with Ne (78.6±1.6 to
88.2±0.9) while least for Xe ion implanted samples (86.9±1.0 to 88.8±2.1).
 The in vitro cell adhesion test: differences between ion implanted samples and the
control untreated samples occurred in the short time, i.e. at 4 hours rather than at 24
hours, suggesting that nano-roughness could be related to early cell attachment.
 1Ne40, 2Ne40, 1Kr40, 2Kr40, 1Xe40 and 2Xe40 samples showed statistically strongly
significant differences (p<0.01) at 4 hours as compared to untreated Ti.
Tissue integration.
Neutral (Ne,Ar,Xe,Kr) ion implantation vs. cells.
[Applied Surface Science, 27 March 2014. http://dx.doi.org/10.1016/j.apsusc.2014.03.118]
.]

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Iñigo Braceras - inigo.braceras@tecnalia.com
TECNALIA
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T: +34 943 105 101

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