In-vitro to In-vivo Correlation of Corrosion in Nitinol - - PowerPoint PPT Presentation

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In-vitro to In-vivo Correlation of Corrosion in Nitinol - - PowerPoint PPT Presentation

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In-vitro to In-vivo Correlation of Corrosion in Nitinol Cardiovascular Stents Stacey J.L. Sullivan 1 Daniel Madamba 2 Shiril Sivan 1 Katie Miyashiro 2 Maureen L. Dreher 1 Christine Trpanier 2 Srinidhi Nagaraja 1 1 Office of Science and

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In-vitro to In-vivo Correlation of Corrosion in Nitinol Cardiovascular Stents

Stacey J.L. Sullivan1 Daniel Madamba2 Shiril Sivan1 Katie Miyashiro2 Maureen L. Dreher1 Christine Trépanier2 Srinidhi Nagaraja1

1Office of Science and Engineering Laboratories; FDA Center for Devices & Radiological Health 2Confluent Medical Technologies

May 19, 2017

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In-vivo Corrosion

Stent Corrosion Testing Paradigm

FDA guidance document Select Updates for Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems

? ? ?

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  • ASTM F2129 not

intended to represent in-vivo conditions

  • Results difficult to

correlate with in-vivo performance

  • Variability in

breakdown potentials from workshop respondents

Proposed Acceptance Criteria Eb > 600 mV à Acceptable Eb = 300-600 mV à Marginal Eb < 300 mV à Unacceptable

Rosenbloom and Corbett, 2007

Motivation

2012 FDA Corrosion Workshop Nagaraja et al., 2016

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Objectives

  • 1. Manufacture and characterize Nitinol stents

manufactured to possess low to high corrosion resistance (ASTM F2129)

  • 2. Investigate in-vivo pitting corrosion of Nitinol

stents manufactured to possess low to high corrosion resistance

  • 3. Correlate in-vitro nickel leaching with in-vivo

release and biocompatibility in Nitinol stents with low to high corrosion resistance

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Group SP Salt Pot MP Mechanical Polish AF Air Furnace OT Oxidized Tubing Tubing

  • Ground
  • Honed

As –received Laser Cut Heat Affected Zone

  • Honed
  • Debur & Deslug
  • Chemically Polish

(no processing) Stress Relief 505°C Salt Pot 540°C Air furnace 505°C Salt Pot Expansion 505°C Salt Pot 505°C Air furnace 505°C Salt Pot Af Tuning 505°C Salt Pot 550°C Air furnace 505°C Salt Pot Finishing Ultrasonic clean

  • Ultrasonic clean
  • Chemical Etch
  • Chemical Polish
  • Burnish
  • Ultrasonic clean

Ultrasonic clean Visual Appearance

Stent Manufacturing Process

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OSS Stent FEA – Crimping & Deployment

à High strain regions at the apex of V-struts

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Methods

In-vivo

  • Minipig implantation:
  • left and right iliac arteries
  • 12 animals implanted
  • Single stent conditions (n=6/group)
  • 6 month implantation period
  • Explanted stent surface analysis
  • SEM and EDS

In-vitro

  • Surface characterization à SEM/Auger
  • Pitting corrosion à ASTM F2129
  • Uniform corrosion à Nickel leach
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In-vitro Testing

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Surface Characterization - SEM

  • Mech. Polish (medium F2129)

Air Furnace (low F2129) Salt Pot (high F2129) Oxidized Tubing (low F2129)

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  • Mech. Polish

Air Furnace Salt Pot

Ni rich region Complex oxide, Ni rich region

Oxide Thickness ~ 4 nm Oxide Thickness ~ 132 nm Oxide Thickness ~ 432 nm

Oxidized Tubing

Oxide Thickness ~ 400 nm

Ni rich region

Surface Characterization - Auger

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High Eb Low Eb

Air Furnace Oxidized Tubing Mech Polish Salt Pot

ASTM F2129 Testing

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n=8-14/group

OT AF MP SP 1000 900 800 700 600 500 400 300 200 100 Eb

Eb

SP MP AF OT

Voltage (mV vs SCE)

OT AF MP SP 1400 1200 1000 800 600 400 200

Voltage (mV vs. SCE )

Eb-Er

SP MP AF OT

Voltage (mV vs SCE)

SP MP AF OT Er(mV)

  • 224 ± 112
  • 103 ± 65
  • 141 ± 44
  • 230 ± 178

Eb(mV) 975 ± 94 767 ± 226 111 ± 63 68 ± 29 Eb-Er(mV) 1199 ± 118 870 ± 240 252 ± 90 297 ± 165

ASTM F2129 Results

95% confidence interval

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  • OT, AF, SP, and MP stents (8 X 30mm) immersed in PBS at 37C
  • Stents crimped prior to testing
  • 10 time points: Day 1, 2, 3, 5, 7, 14, 21, 30, 45, 60
  • Ni release: OT > SP > AF > MP for all time points (*p<0.001)
  • ASTM F2129 breakdown potentials not correlated to Ni release

Sullivan et al., 2015

OT SP AF MP

(n=5/group)

Nickel Leach Testing and Results

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Explant Analysis

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àDeformation, but no fractures observed in explants

Proximal Distal Proximal Distal

In-Situ Imaging

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16 1 10 100 1,000 10,000

SP MP AF OT Ni Release (ppb)

Explanted Artery (180 days)

1 10 100 1,000 10,000

SP MP AF OT Ni Release (ppb)

Explanted Artery (180 days) Bench Testing (60 days)

Arterial tissue surrounding stent digested using papain

à Artery nickel: OT > AF > SP > MP à Explanted artery Ni values variable compared to in-vitro results

(n=3-5/group)

Explanted Artery Nickel

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à No corrosion observed in explanted SP stents

Non-implanted Explant

Ni/Ti n SP Non-implanted 1.12

+/- 0.06

13 SP Explants 1.13

+/- 0.04

36

SEM Imaging – Salt Pot (high F2129)

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Explant Non-implanted

à No corrosion observed in explanted MP stents

Ni/Ti n MP Non-implanted 1.11

+/- 0.01

14 MP Explants 1.11

+/- 0.03

47

SEM Imaging – Mech. Polish (medium F2129)

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Non-implanted Explant

SEM Imaging – Air Furnace (low F2129)

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à Micro-cracks & corrosion observed in explanted AF stents

Ni/Ti 1.01- 1.06 Ni/Ti 0.81- 0.89 Ni/Ti 1.06 Ni/Ti 0.90 Ni/Ti n AF Non-implanted 1.11

+/- 0.02

13 AF Explants - Native Surface 1.08

+/- 0.05

22 AF Explants – Corrosion 0.89

+/- 0.15

24

SEM Imaging – Air Furnace (low F2129)

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Non-implanted Explant

SEM Imaging – Oxidized Tubing (low F2129)

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Ni/Ti 1.06

à Pitting observed in explanted OT stents

Ni/Ti n OT Non-implanted 1.16

+/- 0.10

20 OT Explants - Native Surface 1.05

+/- 0.31

32 OT Explants – Corrosion 1.14

+/- 0.11

59 Ni/Ti 1.22-1.26 Ni/Ti 1.15-1.20 Ni/Ti 1.0-1.38 Ni/Ti 1.06-1.09 Ni/Ti 0.98-1.15

SEM Imaging – Oxidized Tubing (low F2129)

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OT Stent AF Stent

AFà ~1 micron deep corrosion OTà ~9 micron deep pits

Corrosion Depth (FIB milling)

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0.2 0.4 0.6 0.8 1 1.2 1.4

SP

Ni/Ti ratio

Non- implanted Explant - General Explant - Corrosion Explant - Pitting OT MP AF

  • SP and MP explants: no change in Ni/Ti ratios
  • AF explants: sig. lower Ni/Ti ratios in corroded regions
  • OT explants: similar Ni/Ti ratios in corroded regions

* p ≤ 0.05

* * *

Elemental Analysis Summary

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Discussion

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Bench Testing Correlations

  • Ni release (uniform corrosion) is not correlated to breakdown

potentials from ASTM F2129 testing

  • Oxide thickness and composition provides insight into Ni release

Conclusions

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In-vivo Corrosion

Discussion

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Bench Testing Correlations

  • Ni release (uniform corrosion) is not correlated to breakdown

potentials from ASTM F2129 testing

  • Oxide thickness and composition provides insight into Ni release

In-vitro to In-vivo Correlations

  • Ni release
  • In-vitro: OT > SP > AF > MP (uniform corrosion)
  • In-vivo: OT > AF > SP > MP (localized + uniform corrosion)
  • Pitting Corrosion
  • Eb > ~600 mV à no localized corrosion observed
  • Eb < ~200 mV à localized corrosion observed

Conclusions

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SLIDE 29

29

  • Matthew Di Prima, PhD
  • Phillip Stafford, PhD
  • Elon Malkin, PhD
  • Jiwen Zheng, PhD
  • Ramesh Marrey, PhD
  • Chris Lasley
  • Ron Waxman, MD
  • David Hellinga, MS

Acknowledgements

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Biologics Overlapped stents

Upcoming features:

OT

Inflammati

  • n

MP SP AF

Inflammati

  • n
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Bench Testing Correlations

  • Ni release (uniform corrosion) is not correlated to breakdown

potentials from ASTM F2129 testing

  • Oxide thickness and composition provides insight into Ni release

In-vitro to In-vivo Correlations

  • Ni release
  • In-vitro: OT > SP > AF > MP (uniform corrosion)
  • In-vivo: OT > AF > SP > MP (localized + uniform corrosion)
  • Pitting Corrosion
  • Eb > ~600 mV à no localized corrosion observed
  • Eb < ~200 mV à localized corrosion observed

Conclusions