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 Engineerin...
©. Property of TECNALIA.
Surface Engineering on Medical Devices. Abstract
Medical Devices play an increasingly important r...
©. Property of TECNALIA.
Index
-. Tecnalia.
-. Surface engineering vs. biomedical RTD.
Problems & challenges.
Regulatory a...
©. Property of TECNALIA.
TECNALIA is the first applied
research centre in Spain and one
of the most important in Europe
wi...
©. Property of TECNALIA.
4 APPROACHES TO THE WAY WE WORK WITH COMPANIES
TECHNOLOGICAL
SERVICES //
VENTURES //
TECHNOLOGY
A...
©. Property of TECNALIA.
European main RTO’s Funding Sources
2011 data
With a strong corporate
involvement
In TECNALIA's
r...
©. Property of TECNALIA.
Organised in 7 Business Divisions: we work from the
experience and the expertise we have acquired...
©. Property of TECNALIA.
International
Presence
©. Property of TECNALIA.
Index
-. Tecnalia.
-. Surface engineering vs. biomedical RTD.
Problems & challenges.
Regulatory a...
©. Property of TECNALIA.
Problems & challenges.
Medical Devices: “…any instrument, apparatus, appliance, software, materia...
©. Property of TECNALIA.
With modern protocols, the incidence of infections associated to placement of implants
has become...
©. Property of TECNALIA.
-. The interface biomaterial surface-surrounding tissue is where accidental
contamination can fir...
©. Property of TECNALIA.
Bone ?
-. Bio-nanocomposite made up of an organic fiber matrix (collagen,…) stiffened by ceramic
...
©. Property of TECNALIA.
Human bone AFM
. .
Surface Engineering on Medical Devices.
Problems & challenges.
©. Property of TECNALIA.
Human bone AFM
. .
Surface Engineering on Medical Devices.
Problems & challenges.
©. Property of TECNALIA.
Human bone AFM
. .
Surface Engineering on Medical Devices.
Problems & challenges.
©. Property of TECNALIA.
Human bone AFM
. .
Bone particle sizes:
10-30nm
Surface Engineering on Medical Devices.
Problems ...
©. Property of TECNALIA.
Implants & prostheses:
-. Often Ti & alloys: relatively light & good mechanical prop.
-. Natural ...
©. Property of TECNALIA.
.
Osseo integration depends on: Surface quality
-. Surface chemistry.
HAp, bioactive ceramics,…
T...
©. Property of TECNALIA.
Index
-. Tecnalia.
-. Surface engineering vs. biomedical RTD.
Problems & challenges.
Regulatory a...
©. Property of TECNALIA.
Regulatory aspects
… rules relating to the safety and performance of medical devices were harmoni...
©. Property of TECNALIA.
Regulatory aspects
Some key issues:
• Identify Directives and Regulations: Is it really a medical...
©. Property of TECNALIA.
Regulatory aspects
Some key issues:
• How to “build” the Technical File demonstrating compliance?...
©. Property of TECNALIA.
Regulatory aspects
Some key issues:
• How to “build” the Technical File demonstrating compliance?...
©. Property of TECNALIA.
Index
-. Tecnalia.
-. Surface engineering vs. biomedical RTD.
Problems & challenges.
Regulatory a...
©. Property of TECNALIA.
Economic aspects
Some key issues:
• Medical Devices where the technology could be implemented?
• ...
©. Property of TECNALIA.
Index
-. Tecnalia.
-. Surface engineering vs. biomedical RTD.
Problems & challenges.
Regulatory a...
©. Property of TECNALIA.
Antimicrobial surfaces.
M&M: Substrate: AISI 316 LVM
Si+ ion implantation.
Ref: Si-I: 5×1016 ions...
©. Property of TECNALIA.
Antimicrobial surfaces.
Bacteriostatic surfaces:
ion implantation of Si.
Biocompatibility:
Bacter...
©. Property of TECNALIA.
Index
-. Tecnalia.
-. Surface engineering vs. biomedical RTD.
Problems & challenges.
Regulatory a...
©. Property of TECNALIA.
Antimicrobial surfaces.
Drug released: ciprofloxacin
M&M process parameters
Precursor: N,O-bis-te...
©. Property of TECNALIA.
Antimicrobial surfaces.
Tests / results.
Antimicrobial surfaces. Plasma Polymerized Silylated Cip...
©. Property of TECNALIA.
Antimicrobial surfaces.
Tests / results.
Antimicrobial surfaces. Plasma Polymerized Silylated Cip...
©. Property of TECNALIA.
Antimicrobial surfaces.
Tests / results.
 An antibiotic, ciprofloxacin, has been disilylated and...
©. Property of TECNALIA.
Index
-. Tecnalia.
-. Surface engineering vs. biomedical RTD.
Problems & challenges.
Regulatory a...
©. Property of TECNALIA.
Antimicrobial surfaces.
Prof of concept:
A) Plasma polymerization.
B) Vancomycin modification wit...
©. Property of TECNALIA.
Antimicrobial surfaces.
Antimicrobial surfaces. A “Plasma-Click” Dual Procedure
M&M:
A) Plasma su...
©. Property of TECNALIA.
Antimicrobial surfaces.
Antimicrobial surfaces. A “Plasma-Click” Dual Procedure
~1706 cm-1 C=O
~ ...
©. Property of TECNALIA.
Ion implantation and plasma based processes on Medical Devices Antimicrobial surfaces.
Antimicrob...
©. Property of TECNALIA.
Ion implantation and plasma based processes on Medical Devices Antimicrobial surfaces.
Antimicrob...
©. Property of TECNALIA.
Antimicrobial surfaces.
Antimicrobial surfaces. A “Plasma-Click” Dual Procedure
M&M:
B) Vancomyci...
©. Property of TECNALIA.
Antimicrobial surfaces.
Antimicrobial surfaces. A “Plasma-Click” Dual Procedure
M&M:
C) “Click” c...
©. Property of TECNALIA.
Ion implantation and plasma based processes on Medical Devices Antimicrobial surfaces.
Antimicrob...
©. Property of TECNALIA.
Ion implantation and plasma based processes on Medical Devices Antimicrobial surfaces.
Antimicrob...
©. Property of TECNALIA.
Antimicrobial surfaces.
Antimicrobial surfaces. A “Plasma-Click” Dual Procedure
Conclusions: A “p...
©. Property of TECNALIA.
Index
-. Tecnalia.
-. Surface engineering vs. biomedical RTD.
Problems & challenges.
Regulatory a...
©. Property of TECNALIA.
Tissue integration
Tissue integration.
CO ion implanted implantable musculoeskeletal implants.
.....
©. Property of TECNALIA.
AFM
surface
topography
Ref. E
Ref. A Ref.B
Ref. C Ref. D
Ref. E
Ref. A Ref.B
Tissue integration
S...
©. Property of TECNALIA.
In vitro cell culture tests:
-. Cell attachment.
-. Cell proliferation [Surf. Coat Tech vol. 196 ...
©. Property of TECNALIA.
In vitro culture tests
Cell attachment.
 16 samples of each i.i. & ctrol Ti discs,
 Sterilized ...
©. Property of TECNALIA.
Cell proliferation.
 Seeded at conc. of 2,5 e4 cell/well
 Sterilized by UV light
 placed indiv...
©. Property of TECNALIA.
ESEM
AFM
Cell morphology.
Tissue integration
Surface Engineering on Medical Devices.
©. Property of TECNALIA.
Cell apoptosis.
 Seeded at a conc. of 6 x 105 cell/well
 Sterilized by UV light
 placed indivi...
©. Property of TECNALIA.
Alkaline Phosphatase
0
0,5
1
1,5
2
2,5
3 days 8 days 16 days
RelativeALPactivity
Ion implanted
Co...
©. Property of TECNALIA.
In vitro cell culture tests. Conclusions:
• Results depend on the treatment parameters.
• Osteobl...
©. Property of TECNALIA.
In vivo tests on dental implants.
What’s a dental implant?
Typically a Ti/Ti alloy screw replacin...
©. Property of TECNALIA.
How does it work ?
1. Insertion of the implant into the bone.
2. Integration on the surrounding b...
©. Property of TECNALIA.
Treatment example.
From www.oral-implants.com
Tissue integration
Surface Engineering on Medical D...
©. Property of TECNALIA.
Osseointegration (%)
30%
40%
50%
60%
70%
80%
90%
on Ti6Al4V on CPTi
Lifenova
Untreated
Osseointeg...
©. Property of TECNALIA.
i) Test procedure & ethical committee (Univ. Barcelona)
ii) 12 implants x 6 different surfaces.
i...
©. Property of TECNALIA.
BIC %, ESEM evaluation.
0%
10%
20%
30%
40%
50%
60%
70%
80%
Ion implantation Control Commercial
av...
©. Property of TECNALIA.
BIC %, histological evaluation.
0%
10%
20%
30%
40%
50%
60%
70%
80%
Ion implantation Control Comme...
©. Property of TECNALIA.
ESEM-EDS.
Tissue integration
Surface Engineering on Medical Devices.
©. Property of TECNALIA.
ESEM-EDS.
Implant
Mature
bone
New
bone
[International Journal of Oral and Maxillofacial Surgery, ...
©. Property of TECNALIA.
BIC %
0
10
20
30
40
50
60
70
0 Month 1 Month 3 Month 6
Ion implanted Commercial Average Control
T...
©. Property of TECNALIA.
N patients: 19
N of mini-implants: 22
Inclusion criteria:
Healthy patients from both sexes, under...
©. Property of TECNALIA.
Participating Clinics
Pr. Dr. C Gay Escoda. University of Barcelona, Faculty of Odontology.
Dr. M...
©. Property of TECNALIA.
1.8 mm diameter
5 mm long
Clinical trial 277/06/EC
Tissue integration
Surface Engineering on Medi...
©. Property of TECNALIA.
Surgery: drilling.
Tissue integration
Surface Engineering on Medical Devices.
©. Property of TECNALIA.
Surgery: implant insertion.
Tissue integration
Surface Engineering on Medical Devices.
©. Property of TECNALIA.
Surgery: implant extraction.
Tissue integration
Surface Engineering on Medical Devices.
©. Property of TECNALIA.
Surgery: implant extraction.
Tissue integration
Surface Engineering on Medical Devices.
©. Property of TECNALIA.
Histomorphometric study.
Tissue integration
Surface Engineering on Medical Devices.
©. Property of TECNALIA.
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 ...
©. Property of TECNALIA.
Human bone on implant surface AFM
. .
Tissue integration
Surface Engineering on Medical Devices.
©. Property of TECNALIA.
Human bone on implant surface AFM
. .
Tissue integration
Surface Engineering on Medical Devices.
©. Property of TECNALIA.
Conclusions:
-. Higher osseointegration on poor bone density areas.
-. Faster osseointegration th...
©. Property of TECNALIA.
Tissue integration
Tissue integration.
Neutral (Ne,Ar,Xe,Kr) ion implantation vs. cells.
Surface ...
©. Property of TECNALIA.
Tissue integration.
TiGr4, 1Ne40
TiGr4, 1Ne80
TiGr4, 2Ne40
TiGr4, polished
M&M:
Ion implantation ...
©. Property of TECNALIA.
M&M:
Ion implantation of Ar.
1×1017 and 2×1017 ions/cm2,
40keV and 80keV.
Tissue integration.
TiG...
©. Property of TECNALIA.
M&M:
Ion implantation of Kr.
1×1017 and 2×1017 ions/cm2,
40keV and 80keV.
Tissue integration.
TiG...
©. Property of TECNALIA.
Ion implantation and plasma based processes on Medical Devices
M&M:
Ion implantation of Xe.
1×101...
©. Property of TECNALIA.
.
Tissue integration / regeneration.
TiGr4, 1Xe80
TiGr4, 1Xe40
TiGr4, 2Xe40
TiGr4, 1Ar80
TiGr4, 1...
©. Property of TECNALIA.
Tests / results:
Wettability and roughness:
Tissue integration.
75
77
79
81
83
85
87
89
91
93
95
...
©. Property of TECNALIA.
Ion implantation and plasma based processes on Medical Devices
Tests / results:
Cell culture and ...
©. Property of TECNALIA.
Ion implantation and plasma based processes on Medical Devices
Tests / results:
 The contact ang...
©. Property of TECNALIA.©. Propiedad de TECNALIA.
Ion implantation and plasma based processes on Medical Devices
Thanks fo...
Surface Enginnering on Medical Devices.
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Surface Enginnering on Medical Devices.

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Seminário proferido por Iñigo Braceras Izagirre, do Centro de P,D e I TECNALIA (San Sebastián, Espanha) na seção UCS do Instituto Nacional de Engenharia de Superfícies, no dia 17 de abril para um público de cerca de 30 estudantes e professores.

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Surface Enginnering on Medical Devices.

  1. 1. Surface Engineering on Medical Devices. Caxias do Sul 17/04/2014
  2. 2. ©. 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.
  3. 3. ©. Property of TECNALIA. 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.
  4. 4. ©. Property of TECNALIA. 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. Surface Engineering on Medical Devices.
  5. 5. ©. Property of TECNALIA. TECNALIA is the first applied research centre in Spain and one of the most important in Europe with around 1.400 staff, 110 million Euro turnover and over 4.000 clients. A unique commitment, an opportunity, a challenge.
  6. 6. ©. Property of TECNALIA. 4 APPROACHES TO THE WAY WE WORK WITH COMPANIES TECHNOLOGICAL SERVICES // VENTURES // TECHNOLOGY AND INNOVATION STRATEGY // R&D PROJECTS // YOUR PROJECT
  7. 7. ©. Property of TECNALIA. European main RTO’s Funding Sources 2011 data With a strong corporate involvement In TECNALIA's representation, administration and management. In the strategic market orientation of our divisions. In strategic and investment planning. In the development and financing of collaborative activities. In business creation.
  8. 8. ©. Property of TECNALIA. Organised in 7 Business Divisions: we work from the experience and the expertise we have acquired in the markets in which we operate, with an efficient and proactive attitude.
  9. 9. ©. Property of TECNALIA. International Presence
  10. 10. ©. Property of TECNALIA. 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. Surface Engineering on Medical Devices.
  11. 11. ©. Property of TECNALIA. Problems & challenges. 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. Surface Engineering on Medical Devices.
  12. 12. ©. Property of TECNALIA. 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. Problems & challenges. Surface Engineering on Medical Devices.
  13. 13. ©. Property of TECNALIA. -. 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. Problems & challenges. Surface Engineering on Medical Devices. Infections vs. antimicrobial surfaces.
  14. 14. ©. Property of TECNALIA. 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 Surface Engineering on Medical Devices. Problems & challenges. Tissue integration / regeneration vs. osseoinductive surfaces
  15. 15. ©. Property of TECNALIA. Human bone AFM . . Surface Engineering on Medical Devices. Problems & challenges.
  16. 16. ©. Property of TECNALIA. Human bone AFM . . Surface Engineering on Medical Devices. Problems & challenges.
  17. 17. ©. Property of TECNALIA. Human bone AFM . . Surface Engineering on Medical Devices. Problems & challenges.
  18. 18. ©. Property of TECNALIA. Human bone AFM . . Bone particle sizes: 10-30nm Surface Engineering on Medical Devices. Problems & challenges.
  19. 19. ©. Property of TECNALIA. 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 Tissue integration / regeneration vs. osseoinductive surfaces Surface Engineering on Medical Devices. Problems & challenges.
  20. 20. ©. Property of TECNALIA. . 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 “ Problems & challenges. Tissue integration / regeneration vs. osseoinductive surfaces Surface Engineering on Medical Devices.
  21. 21. ©. Property of TECNALIA. 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. Surface Engineering on Medical Devices.
  22. 22. ©. Property of TECNALIA. 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. Surface Engineering on Medical Devices.
  23. 23. ©. Property of TECNALIA. 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. Surface Engineering on Medical Devices.
  24. 24. ©. Property of TECNALIA. Regulatory aspects Some key issues: • How to “build” the Technical File demonstrating compliance? 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. Surface Engineering on Medical Devices.
  25. 25. ©. Property of TECNALIA. Regulatory aspects Some key issues: • How to “build” the Technical File demonstrating compliance? Testing program? = RTD testing? Harmonized standards? Quality System in compliance with ISO 13485? Regulatory aspects. Surface Engineering on Medical Devices.
  26. 26. ©. Property of TECNALIA. 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. Surface Engineering on Medical Devices.
  27. 27. ©. Property of TECNALIA. 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. Surface Engineering on Medical Devices. Intellectual property rights. Some key issues: • Freedom to operate? • Effective protection? • Time to market vs. patent life?
  28. 28. ©. Property of TECNALIA. Index -. Tecnalia. -. Surface engineering vs. biomedical RTD. Problems & challenges. Regulatory aspects. Economic aspects. Intellectual property rights. Case studies. i) Antimicrobial surfaces. Ion implantation Antibiotic release Plasma+click attachment ii) Tissue integration/regeneration. Surface Engineering on Medical Devices.
  29. 29. ©. Property of TECNALIA. Antimicrobial surfaces. 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. Surface Engineering on Medical Devices.
  30. 30. ©. Property of TECNALIA. Antimicrobial surfaces. 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. Surface Engineering on Medical Devices. [Applied Surface Science, In Press, Accepted Manuscript, Available online 4 April 2014]
  31. 31. ©. Property of TECNALIA. Index -. Tecnalia. -. Surface engineering vs. biomedical RTD. Problems & challenges. Regulatory aspects. Economic aspects. Intellectual property rights. Case studies. i) Antimicrobial surfaces. Ion implantation Antibiotic release Plasma+click attachment ii) Tissue integration/regeneration. Surface Engineering on Medical Devices.
  32. 32. ©. Property of TECNALIA. Antimicrobial surfaces. 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 Surface Engineering on Medical Devices.
  33. 33. ©. Property of TECNALIA. Antimicrobial surfaces. Tests / results. Antimicrobial surfaces. Plasma Polymerized Silylated Ciprofloxacin Surface Engineering on Medical Devices.
  34. 34. ©. Property of TECNALIA. Antimicrobial surfaces. Tests / results. Antimicrobial surfaces. Plasma Polymerized Silylated Ciprofloxacin Surface Engineering on Medical Devices.
  35. 35. ©. Property of TECNALIA. Antimicrobial surfaces. 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. Antimicrobial surfaces. Plasma Polymerized Silylated Ciprofloxacin Surface Engineering on Medical Devices.
  36. 36. ©. Property of TECNALIA. Index -. Tecnalia. -. Surface engineering vs. biomedical RTD. Problems & challenges. Regulatory aspects. Economic aspects. Intellectual property rights. Case studies. i) Antimicrobial surfaces. Ion implantation Antibiotic release Plasma + click attachment ii) Tissue integration/regeneration. Surface Engineering on Medical Devices.
  37. 37. ©. Property of TECNALIA. Antimicrobial surfaces. 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 Surface Engineering on Medical Devices.
  38. 38. ©. Property of TECNALIA. Antimicrobial surfaces. 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 Surface Engineering on Medical Devices.
  39. 39. ©. Property of TECNALIA. Antimicrobial surfaces. Antimicrobial surfaces. A “Plasma-Click” Dual Procedure ~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: A) Plasma surface modification. Characterization: FTIR. Ref. CO2H-1 CO2H-2 CO2H-0 Surface Engineering on Medical Devices.
  40. 40. ©. Property of TECNALIA. Ion implantation and plasma based processes on Medical Devices Antimicrobial surfaces. Antimicrobial surfaces. A “Plasma-Click” Dual Procedure M&M: A) Plasma surface modification. 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.
  41. 41. ©. Property of TECNALIA. Ion implantation and plasma based processes on Medical Devices Antimicrobial surfaces. Antimicrobial surfaces. A “Plasma-Click” Dual Procedure M&M: B) Vancomycin modification with azide linker. 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. .
  42. 42. ©. Property of TECNALIA. Antimicrobial surfaces. Antimicrobial surfaces. A “Plasma-Click” Dual Procedure M&M: B) Vancomycin modification with azide linker. 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. Surface Engineering on Medical Devices.
  43. 43. ©. Property of TECNALIA. Antimicrobial surfaces. Antimicrobial surfaces. A “Plasma-Click” Dual Procedure 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% Surface Engineering on Medical Devices.
  44. 44. ©. Property of TECNALIA. Ion implantation and plasma based processes on Medical Devices Antimicrobial surfaces. Antimicrobial surfaces. A “Plasma-Click” Dual Procedure 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)
  45. 45. ©. Property of TECNALIA. Ion implantation and plasma based processes on Medical Devices Antimicrobial surfaces. Antimicrobial surfaces. A “Plasma-Click” Dual Procedure 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)
  46. 46. ©. Property of TECNALIA. Antimicrobial surfaces. Antimicrobial surfaces. A “Plasma-Click” Dual Procedure 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 Surface Engineering on Medical Devices.
  47. 47. ©. Property of TECNALIA. 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. Ion Implantation Surface Engineering on Medical Devices.
  48. 48. ©. Property of TECNALIA. Tissue integration Tissue integration. CO ion implanted implantable musculoeskeletal implants. .. Surface Engineering on Medical Devices.
  49. 49. ©. Property of TECNALIA. AFM surface topography Ref. E Ref. A Ref.B Ref. C Ref. D Ref. E Ref. A Ref.B Tissue integration Surface Engineering on Medical Devices.
  50. 50. ©. Property of TECNALIA. 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 Surface Engineering on Medical Devices.
  51. 51. ©. Property of TECNALIA. 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 Surface Engineering on Medical Devices.
  52. 52. ©. Property of TECNALIA. Cell proliferation.  Seeded at conc. of 2,5 e4 cell/well  Sterilized by UV light  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 Surface Engineering on Medical Devices.
  53. 53. ©. Property of TECNALIA. ESEM AFM Cell morphology. Tissue integration Surface Engineering on Medical Devices.
  54. 54. ©. Property of TECNALIA. Cell apoptosis.  Seeded at a conc. of 6 x 105 cell/well  Sterilized by UV light  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 Surface Engineering on Medical Devices.
  55. 55. ©. Property of TECNALIA. 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 Surface Engineering on Medical Devices.
  56. 56. ©. Property of TECNALIA. 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 Surface Engineering on Medical Devices.
  57. 57. ©. Property of TECNALIA. 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 Surface Engineering on Medical Devices.
  58. 58. ©. Property of TECNALIA. 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 Surface Engineering on Medical Devices.
  59. 59. ©. Property of TECNALIA. Treatment example. From www.oral-implants.com Tissue integration Surface Engineering on Medical Devices.
  60. 60. ©. Property of TECNALIA. 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 Surface Engineering on Medical Devices.
  61. 61. ©. Property of TECNALIA. 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
  62. 62. ©. Property of TECNALIA. 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 * *
  63. 63. ©. Property of TECNALIA. 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 Surface Engineering on Medical Devices.
  64. 64. ©. Property of TECNALIA. ESEM-EDS. Tissue integration Surface Engineering on Medical Devices.
  65. 65. ©. Property of TECNALIA. ESEM-EDS. Implant Mature bone New bone [International Journal of Oral and Maxillofacial Surgery, 38(3), (2009), 274-278] Tissue integration Surface Engineering on Medical Devices.
  66. 66. ©. Property of TECNALIA. BIC % 0 10 20 30 40 50 60 70 0 Month 1 Month 3 Month 6 Ion implanted Commercial Average Control Tissue integration Surface Engineering on Medical Devices.
  67. 67. ©. Property of TECNALIA. 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 Surface Engineering on Medical Devices.
  68. 68. ©. Property of TECNALIA. 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). Clinical trial 277/06/EC Tissue integration Surface Engineering on Medical Devices.
  69. 69. ©. Property of TECNALIA. 1.8 mm diameter 5 mm long Clinical trial 277/06/EC Tissue integration Surface Engineering on Medical Devices.
  70. 70. ©. Property of TECNALIA. Surgery: drilling. Tissue integration Surface Engineering on Medical Devices.
  71. 71. ©. Property of TECNALIA. Surgery: implant insertion. Tissue integration Surface Engineering on Medical Devices.
  72. 72. ©. Property of TECNALIA. Surgery: implant extraction. Tissue integration Surface Engineering on Medical Devices.
  73. 73. ©. Property of TECNALIA. Surgery: implant extraction. Tissue integration Surface Engineering on Medical Devices.
  74. 74. ©. Property of TECNALIA. Histomorphometric study. Tissue integration Surface Engineering on Medical Devices.
  75. 75. ©. Property of TECNALIA. 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 Surface Engineering on Medical Devices. [International Journal of Oral and Maxillofacial Surgery, 42(7) (2013) 891-896]
  76. 76. ©. Property of TECNALIA. Human bone on implant surface AFM . . Tissue integration Surface Engineering on Medical Devices.
  77. 77. ©. Property of TECNALIA. Human bone on implant surface AFM . . Tissue integration Surface Engineering on Medical Devices.
  78. 78. ©. Property of TECNALIA. 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 Surface Engineering on Medical Devices.
  79. 79. ©. Property of TECNALIA. Tissue integration Tissue integration. Neutral (Ne,Ar,Xe,Kr) ion implantation vs. cells. Surface Engineering on Medical Devices.
  80. 80. ©. Property of TECNALIA. 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 Surface Engineering on Medical Devices.
  81. 81. ©. Property of TECNALIA. 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 Surface Engineering on Medical Devices.
  82. 82. ©. Property of TECNALIA. 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 Surface Engineering on Medical Devices.
  83. 83. ©. Property of TECNALIA. 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.
  84. 84. ©. Property of TECNALIA. . 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 Surface Engineering on Medical Devices.
  85. 85. ©. Property of TECNALIA. 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 Surface Engineering on Medical Devices.
  86. 86. ©. Property of TECNALIA. Ion implantation and plasma based processes on Medical Devices 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. Tissue integration / regeneration.
  87. 87. ©. Property of TECNALIA. Ion implantation and plasma based processes on Medical Devices 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 / regeneration. 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] .]
  88. 88. ©. Property of TECNALIA.©. Propiedad de TECNALIA. Ion implantation and plasma based processes on Medical Devices Thanks for your attention! Obrigado por sua atenção! Contact: Iñigo Braceras - inigo.braceras@tecnalia.com TECNALIA Parque Tecnológico de San Sebastián Mikeletegi Pasealekua, 2 E-20009 Donostia – San Sebastián – Gipuzkoa (Spain) T: +34 943 105 101
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