Materials Clinical Assessment- Nitinol Document

Materials Clinical Assessment- Nitinol

Contents 1

INTRODUCTION ... 3 MO Milling is a medical device company specialising in orthopaedic solutions. It intends to design and manufacture products to assist surgeons in a range of surgical procedures. MO Milling branded as 360 Instruments is a subsidiary of Kico Knee Innovation Company (KICo)... 3

2

PURPOSE ... 3

3

SCOPE ... 3

4

EXECUTIVE SUMMARY ... 4

5

MATERIAL CHARACTERISATION & SELECTION ... 5

6

DEVICE DESIGN OVERVIEW ... 6 6.1

Nitinol Guidewire Device Description ... 6

6.2

Nitinol Guidewire Intended Use ... 6

6.3

360KS Surgical Instruments Indications for Use ... 6

7

DEVICE CATEGORISATION ... 6

8

MATERIAL CHARACTERISATION & SELECTION ... 9 8.1

Material Characterization: Nitinol ... 9

8.1.1

Nickel ... 9

8.1.2

Titanium... 9

8.1.3

Titanium-Nickel Alloy- Nitinol... 10

Alloy Composition ... 10 9

BIOCOMPATIBILITY ... 11

10

BIOLOGICAL RISK EVALUATION ... 12

11

INTERPRETATION OF BIOLOGICAL ENDPOINTS ... 12

11.1

CYTOTOXICITY ... 12

11.2

SENSITISATION ... 13

11.3

INTRACUTANEOUS REACTIVITY ... 13

11.4

SYSTEMIC TOXICITY... 14

11.5

MATERIAL MEDIATED PYROGENICITY ... 14

11.6

ACUTE SYSTEMIC TOXICITY ... 14

11.7

CONCLUSION ... 15

Qualifications of Author ... 16

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Materials Clinical Assessment- Nitinol

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INTRODUCTION MO Milling is a medical device company specialising in orthopaedic solutions. It intends to design and manufacture products to assist surgeons in a range of surgical procedures. MO Milling branded as 360 Instruments is a subsidiary of Kico Knee Innovation Company (KICo). As a medical device company, Kico must ensure that the development of products is compliant with all applicable regional, national regulatory and statutory requirements. This report is to determine the biological safety and assess overall risk of the device in this application based on review of all the available evidence.

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PURPOSE The purpose of this document is to provide a biocompatibility justification of the MO Milling Nitinol Guidewire Class I device to ensure usability and adherence to ISO 10993:2016 in respect of rule 7 of the Essential Principles: Choice of materials ensuring that the requirements of Part 1 are met in relation to a medical device, particular attention must be given to: (a) the chemical and physical properties of the materials used in the device; and (b) the compatibility between the materials used and biological tissues, cells, body fluids and specimens; having regard to the intended purpose of the device

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SCOPE This report applies to the biological evaluation of Mo Milling’s Class I Device- Nitinol Guidewire and material is expected to have direct or indirect contact with the patient during intended use as applicable to ISO 10993 The international consensus standard for biological evaluation is ISO 10993–1:2018 1 Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process. This biological evaluation has been conducted in accordance with the requirements of ISO 10993–1 and with other parts of the ISO 10993 series of standards which provide detailed guidance on all aspects of the biological evaluation. The parts relevant to this evaluation are identified at applicable points in this report.

Published in August, 2018. It should be noted that ISO 10993-1 and other subparts of ISO 10993 have also been published as European harmonized standards in a corresponding EN ISO 10993 series. The technical content of the ISO and EN ISO documents is identical in all ISO 10993 documents referenced in this report and a reference to an ISO 10993 part can also be taken as a reference to its EN ISO equivalent.

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Materials Clinical Assessment- Nitinol

EXECUTIVE SUMMARY

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This biological (biocompatibility) evaluation report provides an assessment of the risk analysis, nonclinical data and benefit pertaining to the Nitinol Guidewires, to determine whether the safety is adequately supported and if the risk: benefit position is favourable for the intended use and indications for use of the device. This biological evaluation report has been undertaken in accordance with: •

ISO 10993-1:2018, Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process.

•

ISO 14971:2007, Medical Device – Application of risk management to medical devices

Evaluation included consideration of: physical characteristics, chemical formulations, degradation processes and products, manufacturing processes, sterilisation means, biological testing, leachable substances, toxicological risk assessment, clinical evidence and benefit assessment. The biological evaluation report establishes that the device is biocompatible in clinical use. The risk assessment determines that the risk is acceptable.

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MATERIAL CHARACTERISATION & SELECTION The physical characteristics of the final product, including density, strength and dimensions are also likely to be relevant to the local tissue responses. ISO/TS 10993–19, Biological evaluation of medical devices - Part 19: Physico–chemical, morphological and topographical characterization of materials provides relevant guidance on this aspect of materials characterization. The chemical characteristics of the final product, including material type, formulation ingredients, chemical composition, reaction products and by products, contaminants, the effects of processing, processing aids and sterilant residues are likely to be relevant to biological responses. ISO 10993-18, Biological evaluation of medical devices – Part 18: Chemical characterisation of materials provides relevant guidance on this aspect of materials characterization. Chemical characterisation shall also include identification of substances that are Carcinogenic, Mutagenic or toxic to Reproduction (CMR), and where possible quantification. Substances known to be endocrine disruptors shall be treated similarly. Nitinol, a metal alloy comprised of nickel and titanium, has been selected to construct the guidewires.

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DEVICE DESIGN OVERVIEW

6.1

Nitinol Guidewire Device Description Nitinol Guidewire is a MO Milling registered Class I device used in the assistance of alignment of instrumentation during thoracolumbar spinal fusion surgery. The guidewires are only to be used by qualified personnel trained in the use of surgical instruments and the relevant surgical procedures.

6.2

Nitinol Guidewire Intended Use

The Guidewire is intended for use as surgically invasive medical device used in the assistance to aid alignment of instrumentation during thoracolumbar spinal fusion surgery. Nitinol guidewire is intended for transient use (<60min) in surgical environments.

6.3

360KS Surgical Instruments Indications for Use

MO Milling Nitinol Guidewires are indicated for us thoracolumbar spinal fusion surgery.

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DEVICE CATEGORISATION Nitinol Guidewire’s TGA Device classification is classified as Class I as per TD-065 Reusable Surgical Instrument Device Classification Nitinol. Additionally the guidewire was classified according to ISO 10993-1: 2018 Biological Evaluation of Medical Devices - Part 1 Evaluation and testing within a risk management process, as per Table 5.1

Table 5-1 Device Categorisation

Section

Categorisation

Justification

5.2.3-Externally communicating medical devices

b) ‘Tissue/bone/dentil’ Medical devices that contact tissue, bone or pulp/dentin systems.

Nitinol Guidewire will contact exposed bone as per prescribed use. Wires will be partially implanted for transient use to provide guidance for screw and other permanent implant fixtures.

5.3.1 Contact duration categories

a) Limited Exposure (A) – medical devices whose cumulative sum of single, multiple or repeated duration of contact is up to 24 h.

Due to the nature of contact, Nitinol Guidewires will contact Tissue/Bone in a Limited Transitory capacity.

5.3.2 Transitory-contacting medical devices

Some medical devices with limited exposure (A) have very brief/transitory contact with the body

Due to the nature of contact, Nitinol Guidewires will contact Tissue/Bone in a Limited Transitory capacity.

•

The transitory contact duration identified for the body contacting component also falls within the category: Limited exposure (A) < 24 h.

•

As per Annex 9 Directive 93/42/EEC CLASSIFICATION CRITERIA I. DEFINITIONS 1. Definitions for the classification rules 1.1. Duration Transient Normally intended for continuous use for less than 60 minutes.

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As per ISO 10993-1:2018, Clause 5.3.2 “Some medical devices with limited exposure (A) have very brief/transitory contact with the body (e.g. lancets, hypodermic needles, capillary tubes that are used for less than one minute). These generally would not require testing to address biocompatibility. However, for products made with materials such as coatings or lubricants that could be left in contact with body tissues after the medical device is removed, it is possible that a more detailed biocompatibility assessment will be necessary. Cumulative se should also be considered.” In summary, per ISO 10993-1:2018, Nitinol Guidewires are intended for use to be a minimally invasive Externally Communicating, Tissue/Bone Contacting, Limited Exposure, Transient use medical device.

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ISO 10993-1:2018(E)

1, 3.6, 3.11: Is there either direct or indirect contact? 4.2, 4.3, 6.1.1, Obtain physical/chemical information. Consider material characterisation 4.3, 6.1 Same as material as in marketed devices (ie same formulation)? 4.3, 6.1 Same geometry and physical properties? 5 Same body contact and clinical use? Perform toxicological risk (assessment Annex B)

yes- Direct Contact. yes- Information was obtained through a literature review of Nitinol, referenced in this report reporting material characteristics deeming Nitinol to be an effective and widely used material for the intended application. yes- Identical material has been reportedly used by Lifehealthcare for the same device and application using the same supplier as per available drawings provided by Lifehealthcare. yes- Design has been reviewed to be identical as per internal design reviews yes- Direct contact, transitory duration, for use with the same LifeHealthcare product. Toxicology risk completed and benefits out weigh any perceived risk as per medical device use.

© 2020, MO Milling. Confidential. Must not to be made available to third parties without prior consent of MO Milling management.

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MATERIAL CHARACTERISATION & SELECTION The physical characteristics of the final product, including density, strength and dimensions are also likely to be relevant to the local tissue responses. ISO/TS 10993–19, Biological evaluation of medical devices - Part 19: Physico–chemical, morphological and topographical characterization of materials provides relevant guidance on this aspect of materials characterization. The chemical characteristics of the final product, including material type, formulation ingredients, chemical composition, reaction products and by products, contaminants, the effects of processing, processing aids and sterilant residues are likely to be relevant to biological responses. ISO 10993-18, Biological evaluation of medical devices – Part 18: Chemical characterisation of materials provides relevant guidance on this aspect of materials characterization. Chemical characterisation shall also include identification of substances that are Carcinogenic, Mutagenic or toxic to Reproduction (CMR), and where possible quantification. Substances known to be endocrine disruptors shall be treated similarly. Nitinol, a metal alloy comprised of nickel and titanium, has been selected to construct the guidewires. Nitinol has been historically used for a broad range of implantable device, so its use for the application of a transient contact guide wire has been deemed appropriate.

8.1

Material Characterization: Nitinol Nitinol is a commonly used material in the manufacturing of medical devices 2, selected for its pseudoplasticity and shape memory behaviour.

8.1.1

Nickel Nickel belongs to the transition metals and is hard and ductile. Nickle is also an essential trace element for humans. Pure Ni can be harmful to the human body in high doses and cause toxic effects such as cancer to allergic reactions. Free Ni atoms of a dangerous level can be accepted into human cell membranes disrupting normal DNA expression and repress damage repair pathways.

8.1.2 Titanium Titanium has excellent corrosion resistance and biocompatibility due to readily forming titanium oxide surface layer. Titanium can also be surface coated with a calcium phosphate (Ca-P) rich layer to promote osseointegration. This material has historically been used in a wide range of implant devices as per ISO 5832-2, Implants for surgery - Metallic materials - Part 2: Unalloyed titanium.

Duerig T, Pelton A, Stockel D. An overview of nitinol medical . applications. Mater Sci Eng 1999;A273–275:149. 2

© 2020, MO Milling. Confidential. Must not to be made available to third parties without prior consent of MO Milling management.

Materials Clinical Assessment- Literature Review

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8.1.3 Titanium-Nickel Alloy- Nitinol Alloying nickel and titanium is known for its ability to produce a metal with shape memory and super-elasticity. Shape memory is limited to alloys with almost equiatomic composition (50% atomic weight). In Nitinol, as the nickel concentration increases the characteristic transformation temperature of the metal decreases. This alloy composition will exhibit transformation from a martensitic to an austenitic microstructure accounting for the shape memory effect. This shape memory effect has been found as advantageous for the development of medical devices, in particular for stent technology. Unlike more complex organic materials (including coatings) metal alloys have a fairly discrete chemical composition, and do not require any information generation.

Alloy Composition Table 5-2. Material Designation

Grade

ASTM F2063 Standard Specification for Wrought Nickel-Titanium Shape Memory Alloys for Medical Devices and Surgical Implants Table 5-3. Material Composition

Element

Ti

Ni

Min

Balance

54.5

Max

57.0

C

Co

Cu

Cr

H

Fe

Nb/Cb

N

O

0.005

0.040

0 0.040

0.50

MO-TD-092 Material Clinical Assessment- Nitinol

0.010

0.010

0.005

0.050

0.025

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BIOCOMPATIBILITY The term ‘biocompatibility’ may be simply defined as the ability of a material to be accepted by the body. Since all materials generate a ‘foreign body reaction’ when implanted in the body, the degree of biocompatibility is related to the extent of this reaction. Therefore, biocompatibility is directly related to the corrosion behaviour of the material in a specified solution and the tendency for the alloy to release potential toxic ions. 3.1 General Literature: Nitinol Additional corrosion resistance and hence biocompatibility advantages are a characteristic of Nitinol 3. The material’s surface actively creates a passive Titanium oxide layer TiO2 which effectively reduces the amount of Ni atoms at the metal surface. This gives the alloy strong corrosion resistance and prevents harmful amounts of Ni to leach into the body 45 . Additional surface heat treatment increases this oxide layer and further passivated release of Ni ions into the surrounding tissue. Nitinol, as discussed, develops a passive titanium oxide layer which forms a stable chemical structure which prevents the release of free Ni or Ti atoms into surrounding tissue. Long term implantation of Nitinol Implants has been accepted as a viable material option for medical devices 6. For example, Nitinol is used in the manufacture of vascular stents 7. These are implantable medical devices that are defined as permanent patient contacting devices. Nitinol is used in heart valve tools, bone anchors, staples, septal defect devices and implants due to its superelastic properties similar to bone. Studies have shown 8 in the short term, nitinol produces no cytotoxic, allergic or genotoxic reactions. Hence it has been noted that nitinol is well tolerated in vitro in comparison with other metals such as stainless steel and pure titanium.

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J. Ryhänen (2000) Biocompatibility of Nitinol, Minimally Invasive Therapy & Allied Technologies, 9:2, 99-105, DOI: 10.3109/13645700009063056 4 Tian, H., Schryvers, D., Liu, D., Jiang, Q., & Van Humbeeck, J. (2011). Stability of Ni in nitinol oxide surfaces. Acta Biomaterialia, 7(2), 892–899. https://doi.org/10.1016/j.actbio.2010.09.009 5 Firstov, G., Vitchev, R., Kumar, H., Blanpain, B., & Van Humbeeck, J. (2002). Surface oxidation of NiTi shape memory alloy. Biomaterials, 23(24), 4863–4871. https://doi.org/10.1016/S0142-9612(02)00244-2 6 Sinha, S., Begam, H., Kumar, V., Nandi, S., Kubacki, J., & Chanda, A. (2018). Improved performance of the functionalized nitinol as a prospective bone implant material. Journal of Materials Research, 33(17), 2554–2564. https://doi.org/10.1557/jmr.2018.204 7 Guhathakurta, S., & Galla, S. (2019). Progress in cardiovascular biomaterials. Asian Cardiovascular and Thoracic Annals, 27(9), 744–750. https://doi.org/10.1177/0218492319880424 8 Mikulewicz, M., & Chojnacka, K. (2011). Cytocompatibility of Medical Biomaterials Containing Nickel by Osteoblasts: a Systematic Literature Review. Biological Trace Element Research, 142(3), 865–889. https://doi.org/10.1007/s12011-010-8798-7

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BIOLOGICAL RISK EVALUATION

As per ISO 13485:2016, the development of the Nitinol Guidewires has been conducted using a riskbased approach. As per ISO 14971 Medical Devices - Application of Risk Management to Medical Devices, a risk management process was undertaken to assess the potential risks associated with the biological evaluation of Nitinol. As part of the design considerations and mitigation activities a Failure Mode and Effects Analysis (FMEA) was conducted on the instruments in a stand-alone document as part of the LHC-NIT-35XXX Range Traceability Matrix. The guiding principle of this plan is to do the most logical test which imposes the least burden and minimises the number of animal experiments and the number of animals involved. For cytotoxicity, sensitisation, intracutaneous reactivity and systemic effects, the test subjects are extracts prepared with both polar and non-polar vehicles. As the exposed surface of the Nitinol Guidewires Instruments are ceramic, and insoluble, no substances will be leached in either polarity of vehicle. Therefore, the bulk of the biological testing is not conducted

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INTERPRETATION OF BIOLOGICAL ENDPOINTS 11.1

CYTOTOXICITY

The effects on cultured mammalian cells of either direct contact, or contact with extracts, from a device material is a sensitive screen for the presence of toxic compounds which may be extracted from a biomaterial and cause adverse effects on living cells. Appropriate methods for testing are provided in EN ISO 10993–5:2009. These methods specify the incubation of cultured cells in contact with extracts of the device. The extraction vehicle in this case is Minimal Essential Medium (MEM), a nutrient culture medium with both polar and non-polar characteristics. This best represents the clinical application of the test article. The selection of cell line is important and should reflect the types of cells present at the site of tissue contact. For materials intended to be implanted into soft tissue, fibroblast cells are commonly chosen as they are ubiquitous in soft tissue and are easily cultured in perpetual cell lines. They are also found in dermal tissue (although it is noted that application for treatment of serious burns will involve direct contact with sub–dermal tissues – the dermal layer having been debrided). The cell line selected for cytotoxicity is Mouse L929 Fibroblasts. This cell line is recommended in EN ISO 10993–5 for assessment of materials to be used in contact with soft tissue. The cells are to be exposed to a series of extracts at different concentrations. Given that the device surface is an insoluble ceramic and that contact is transitory, it is anticipated that test results would show the lowest possible cellular reaction to the test system, Grade 0, no reactivity. Therefore, this test has not been conducted. The test system is dimensionless, and is applicable to any extent of dosage. On this basis there is no risk of a cytotoxic response in a patient from exposure to 360CAS.

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SENSITISATION

Sensitisation is a form of immune response where after an initial exposure to a material, leachable agent or degradation product, the immune system becomes sensitised, leading to a rapid adverse tissue reaction on subsequent exposures. Sensitisation responses may range from mild and localised allergic contact dermatitis to severe and life threatening anaphylactic reactions. Most sensitisation responses to medical devices result from the extractable components of a materials construction. The extracts are always considered to be mixtures. Therefore, sensitisation screening is by means of one of a range of animal tests in which test subjects are exposed to an initial extract followed by a second exposure after a period (6–8 weeks) sufficient for the immune system to develop a full sensitisation. The consensus standard method of choice is the Magnusson Kligman Maximisation test – involving initial intracutaneous exposure of extracts in guinea pigs followed by a second topical exposure and scoring for localised responses at the exposure site. This assay is recommended in ISO 10993–10:2010. It is the most reliable test method for mixtures. Testing is typically performed on both polar extract (saline) and non-polar extract (Cottonseed Oil) thus covering the full range of possible clinical exposures. Given that the device surface is an insoluble ceramic and that contact is transitory, it is anticipated that test results would show the lowest possible reaction in the test animals, 0% sensitised. Therefore, this test has not been conducted. The test system is dimensionless, and is applicable to any extent of dosage. On this basis there is no risk of a sensitisation response in a patient from exposure to 360CAS.

11.3

INTRACUTANEOUS REACTIVITY

Irritation is a local reaction which may be caused by the effects of leachable compounds on the local site of contact. It is of particular importance in contact with mucous membranes or wound sites and therefore needs to be fully investigated given the application is for treatment of burns. This assay is recommended in ISO 10993–10 for irritation testing. The selected protocol involves intracutaneous injection in rabbits of both polar extract (saline) and non-polar extract (Cottonseed Oil) thus covering the full range of possible clinical exposures. The tissue reaction (swelling, redness) over 72 hours is scored and compared to control injections of extraction vehicles alone. Given that the device surface is an insoluble ceramic and that contact is transitory, it is anticipated that test results would show the lowest possible overall mean score in the test animals, 0.0. Therefore, this test has not been conducted. The test system is dimensionless, and is applicable to any extent of dosage. On this basis there is no risk of an irritation response in a patient from exposure to 360CAS.

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SYSTEMIC TOXICITY

Systemic toxicity results from leachables or degradation products being transported from the site of clinical application/exposure to remote tissues and organs via lymphatic or vascular systems. Different effects may occur in relation to initial exposure and to longer term exposure. Therefore, studies should consider both acute and chronic toxic effects using dose rates which reflect likely exposure rates at different time points, with a safety margin (multiple dose) incorporated into the study design. Systemic toxicity is studied by means of in-vivo exposure followed by detailed toxicological examination at several time points. ISO 10993–11 recommends that exposure may be by extract injection (intravenous, intraperitoneal, sub–cutaneous or intramuscular) or by implant of a material sample. Given that the test article is in contact with bone, the most appropriate study design would be an implant model with a duration covering the likely exposure period to the device material. This would result in exposure to leachables in a way most reasonably representative of clinical use. Because systemic toxicity studies are dose related, methods call for implanted quantities such that the dose is a multiple of that anticipated in clinical use (adjusted for body weight of the test animal compared to human).

11.5

MATERIAL MEDIATED PYROGENICITY

Material mediated pyrogenicity is a relatively rare phenomenon. Generally, such pyrogens are due to biologically derived non-endotoxic substances, and are fairly well identified. Examples include: Interleukin 6, Prostaglandin, Polyadenylic acid, opiates, Picric acid, bacterial exotoxins, Serotonin and Nickel (ions). This particular test is normally established employing injectable extract media into a host animal. Given that the device surface is an insoluble ceramic and that contact is transitory, it is anticipated that test results would show that the material is non-pyrogenic. Therefore, this test has not been conducted. On this basis there is no risk of a febrile response in a patient from exposure to 360KS SURGICAL INSTRUMENTS.

11.6

ACUTE SYSTEMIC TOXICITY

Given that the device surface is an insoluble ceramic and that contact is transitory, it is anticipated that testing results would not identify any evidence of systemic toxicity. Therefore, this test has not been conducted. On this basis there is no risk of an acute systemic response in a patient from exposure to 360KS SURGICAL INSTRUMENTS.

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CONCLUSION

The overall interpretation of the endpoints is that the device will not produce observable local or systemic effects in the exposed individual. Additional literature reviews support the safe use of this material for implantable devices further supporting safe historical use in higher risk applications. 910

Nitinol – Its Use in Vascular Surgery and Other Applications C. D. J. Barras and K. A. Myers Thierry B, Merhi Y, Bilodeau L, Trépanier C, Tabrizian M. Nitinol versus stainless steel stents: Acute thrombogenicity study in an ex vivo porcine model. Biomaterials 2002; 23: 2997–3005 9

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Appendix I References

2

7

An overview of nitinol medical appl

3

Biocompatibility of Nitinol.pdf

4

Stability of Ni in Surface oxidation Improved nitinol oxide surface of NiTi shape memor performance of the

Progress in Thierry B, Merhi Y, Cytocompatibility cardiovascular biom of Medical Biomateri Bilodeau L, Trepanie

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9

5

10

6

Nitinol – Its Use in Vascular Surgery and

Qualifications of Author It is a requirement of ISO 14971, ISO 10993 and of medical device regulations that the biological evaluation shall be planned and conducted by personnel with appropriate qualifications and training. This report was prepared by Mr David Tiernan. David Tiernan B.Sc. is qualified in Materials Science receiving a Bachelor of Biomedical and Advanced Materials from the University of Limerick. He has worked in product development, biochemical manufacturing and as a Biocompatibility and toxicology Specialist spanning a career of 10 years.

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