Absorbable Metals Advancements

Adam Griebel
R&D, Fort Wayne Metals
Absorbable Metals
OMTEC 2017 – Raw Material Advancements

Why am I here?
At Fort Wayne Metals,
research and development are keys to the future.
Because the industries we serve are rapidly changing, we must allocate sufficient
resources to develop new products and processes. We are also committed to supporting
our customers’ product development through sample orders and research projects.

Why do we want
Absorbable Metals?

Absorbable metals may…
• Reduce or eliminate:
– Secondary removal operations
– Stress shielding
– Long term complications
– Allergic reactions
• Offer higher strength and toughness over
current absorbable implants
• Improve pediatric care

Envisioned orthopedic applications
• Screws
• Plate & screw systems
– Maxillofacial, hand
• Cerclage
• K-wires/pins/ESIN
• Staples
• Spinal fusion
By Júlio Reis - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=322974

Nutrient Metals
Daily Allowance1: 10-20 mg 15 mg 700 mg
1Y.F. Zheng et al. / Materials Science and Engineering R 77 (2014) 1-34

What’s old is new again
• Magnesium wire for
ligatures in 18781
• Significant Mg usage
up through 1940s2
1. E. Huse, "Magnesium Ligatures," Chic. Med. J. Exam, 37 (1878), 171–172.
2. M.G. Seelig, "A study of magnesium wire as an absorbable suture and ligature
material," Archives of Surgery, 8 (1924), 669–680.

Ideal Progression after Implantation
D Zhao et al. / Biomaterials 112 (2017) 287-302

Corrosion Mechanism
Y.F. Zheng et al. / Materials Science and Engineering R 77 (2014) 1-34

Iron: corrosion too slow
• Ø1.6 mm pins
• Rat femur
• 12 months

Zinc: faster corroding, but…
Bowen et al., Advanced Materials, 2013
• 250 µm wire
• Rat aorta
• 6 months

Magnesium: the best bet
T Kraus et al. / Acta Biomaterialia 8 (2012) 1230-1238
• Ø1.6 mm pins
• Rat femur
• 24 weeks

Mg screws in the clinic
6 weeks 3 months 8 months 17 months
Biber, Trauma Case Reports, 2017
• Syntellix
• CE Marking for Magnezix® compression screw in 2013

Biber, Trauma Case
Reports, 201717 months6 weeks
• Syntellix
• CE Marking for Magnezix® compression screw in 2013

Pre-op T = 0 T = 6 mo T = 1 yr
Lee et al, PNAS 113 (2016) 716-721

Designing with Magnesium
What is important to consider?

Primary considerations
• Mechanical
– Strength (lower)
– Ductility (lower)

• Mechanical
• Corrosion
– In Vitro ≠ In Vivo
– Rate + Type
– Influence of Load
• Stress-Corrosion Cracking
• Corrosion fatigue
H. Kalb et al. / Corrosion Science 57 (2012) 122–130

• Mechanical
• Corrosion
• Biological
– Cell attachment/Cytotoxicity
– Corrosion products
– Rare earths or Aluminum?
J.E. Schaffer et al. / Acta Biomaterialia xxx (2012) xxx–xxx
Turansyaka et al, Materials 2016, 9, 811

• Mechanical
• Corrosion
• Biological
• Intellectual
– Crowded IP landscape

Magnesium Development at
Fort Wayne Metals

Mg @ Fort Wayne Metals
• 4+ years Mg processing research
– Record strength levels
– Developing towards commercial production
• Internal and customer-directed
research
• Experience with 20+ alloys
• Cold work drives strength

Alloy Example: Resoloy®
• Mg-Rare Earth alloy (vascular indication)
Resoloy® is a registered trademark of MeKo, Sarstedt, Germany

Alloy Example: Resoloy®
• Mg-Rare Earth alloy (vascular indication)
0
0.01
0.02
0.03
0.04
0.05
0 10 20 30 40 50dissolvedMg2+[mg/mm2]
time (h)
500°C
450°C
400°C
50% CW
350°C
250°C
t = 0
hrs
t = 45
hrs
Resoloy® is a registered trademark of MeKo, Sarstedt, Germany

Future Directions
• Continue towards commercial scale
• Cold-work impact on corrosion
• Influence of coatings & surface modifications
• Device-specific property tuning

In Summary
• Absorbable metals can offer real benefits
• Magnesium is most promising for
orthopedic applications
• Inquiries: adam_griebel@fwmetals.com

Biocompatibility of
Titanium MIM

Praxis Overview
• Contract manufacturer of titanium components
• Solely focus on titanium PM
• Manufacturing implantable components since 2008
• ISO 13485 Certified | Production and Design
• FDA Registered
OMTEC 2017

Pros & Cons of MIM implants
• Supply chain / purchasing
• Cost savings!
• Product development
• Design flexibility
• Regulatory / validation
• New process
• Density and potential pores
• New materials
• Processing aids
OMTEC 2017

Material Specifications
Standard
Element / Property ASTM F2885-11 ASTM F136-13
MIM Wrought
Nitrogen 0.05% max 0.05% max
Carbon 0.08% max 0.08% max
Hydrogen 0.015% max 0.012% max
Iron 0.30% max 0.25% max
Oxygen 0.20% max 0.13% max
Aluminum 5.5 – 6.75% 5.5 – 6.5%
Vanadium 3.5 – 4.5% 3.5 – 4.5%
Yttrium 0.005% N/A
Titanium* Balance Balance
Ultimate Tensile
Strength
900 MPa min 860 MPa min
Yield Strength 830 MPa min 795 MPa min
Elongation 10% min 10% min
Reduction of Area 15% min 25% min
OMTEC 2017

Praxis MIM Ti-6Al-4V
Property ASTM F2885-11
Requirement
Capability (Ppk)
Nitrogen <0.05 5.17
Carbon <0.08 2.38
Hydrogen <0.015 2.03
Iron <0.30 2.73
Oxygen <0.20 1.58
Aluminum 5.5 - 6.75 1.87
Vanadium 3.5 – 4.5 6.25
Yttrium <0.005 below detection limits
Titanium Balance Not required
Long term capability
Near 6σ
Process capability
Property
ASTM F2885
Min. Requirement
Min. Result Ppk Result
UTS (ksi) 130 139.0 25.29
Yield (ksi) 120 121.8 1.6
Elongation (%) 10 18 3.2
Reduction in Area (%) 15 30 3.14
OMTEC 2017

Praxis MIM Ti-6Al-4V
Property ASTM F2885 Requirement
Min.
Result
Ppk
Result
Final Density (%) 98 min 99.81 5.63
As-Sintered >95% dense HIP’d ~100% dense
OMTEC 2017

‘Net-shape’ MIM Process
Process Raw materials & processing aids
Feedstock formulation Powders & binders
Injection molding Mold releases
Debinding Solvents
Sintering Ceramics & process gases
Recurring questions:
How do you know all the binder is out?
What about residuals?
Is final chemistry really sufficient?
OMTEC 2017

Beyond ‘net-shape’ MIM
Potential secondary operation Processing materials
CNC machining Cutting tools & cutting fluids
Polishing & grinding Media & compounds
Passivation & anodization Acids & solvents
OMTEC 2017

Remove the concern, reduce the risk…
Consistent hesitation from medical OEMs and
potential significant delays
Solution
Conduct testing and create an FDA master file
that addresses their concerns
OMTEC 2017

Guidance – ISO 10993
OMTEC 2017

Overview of testing for FDA master file
Risk assessment
• Raw material properties
• Manufacturing material properties
• Manufacturing methods
• Final MIM component composition
and physical properties
• Biocompatibility of MIM components
• Sterilization compatibility – not included
OMTEC 2017

Test results
Cytotoxicity
• The quality of being toxic to cells
• Test: Minimal Essential Media (MEM) Elution test
• Used to determine cytotoxicity of extractable substances
• Cell monolayers are used to determine
degree of cellular destruction
• Score 0-4: no effect to complete destruction
• Results
• ‘0’ – Passed, no cell degradation
OMTEC 2017

Test results
Sensitization
• Allergic reaction of an irritant
• Test: Guinea Pig Maximization Sensitization Test
• Used to determine dermal sensitization reaction
• 34 guinea pigs, 22 in test group, 12 in control group
• Score 0-3: no reaction to swelling
• Results
• ‘0’ – Passed, no sensitization
OMTEC 2017

Test results
Irritation or intracutaneous reactivity
• Irritation reaction when injected intracutaneously
• Test: Intracutaneous reactivity Irritation test in rabbits
• Tissue reaction (erytherma and edema) with 2 solutions
containing saline or cottonseed oil
• 3 rabbits, 5 sites per rabbit @ 24, 48 & 72 hrs after dose
administration
• Score 0-4 for both erytherma & edema: total max score of 8
• Results
• ‘0’ for saline and ‘0.1’ for cottonseed oil
• Passed, no irritation
OMTEC 2017

Test results
Acute systemic toxicity
• Systemic toxicity of leachable compounds
from test article
• Test: Medical device acute systemic toxicity test in mice
• 2 solutions containing saline or cottonseed oil
• 20 mice, 5 per test group, 2 control and 2 extract groups
• Classification: no side effects to mortality
• Results
• Passed, ‘no side effects’
Note: subacute/subchronic toxicity tests were not conducted
OMTEC 2017

Test results
Genotoxicity
• Destructive effect on a cell’s genetic material (DNA, RNA)
• Test: Ames Test
• Determines mutagenic activity of a solid test article extract by
exposing a large number of test organisms to the extract fluid
in agar plates
• Results: calculated using a validated computer program
• Results
• Passed, ‘extracts did not meet the criteria
for a potential mutagen’
OMTEC 2017

Test results
Genotoxicity
• Destructive effect on a cell’s genetic material (DNA, RNA)
• Test: Chromosome aberration assay
• Determines if device causes structural chromosome
aberrations in Chinese Hamster Ovary (CHO) cells
• Positive control and test article compared to negative
control using Chi-Square test
• Results calculated using a validated computer program
• Results
• Passed, ‘test article is not considered to be genotoxic when
exposed to CHO cells’
OMTEC 2017

Test results
Implantation
• Test: Rabbit tibia implant – 13 wk & 26 wk
• Determines if medical device surgically implanted in
rabbit tibia produces a local tissue reaction
• 6 rabbits (each test): test article versus control (HDPE)
• Irritation ranking: 0-4
• Results
• Passed, ‘test article did not cause any tissue irritation;
considered a non-irritant and is considered biocompatible’
OMTEC 2017

Thank you
OMTEC 2017
Jobe Piemme
Vice President, Business Development
Praxis Technology
jpiemme@praxisti.com
518-812-0112

Jeff Tyber, MS: CEO/President
Dan Hickey, PhD: Postdoctoral Scientist
Providing Rapid Access to Portfolio Enhancing, Regulatory Approved, Orthopedic Implants
Surface Modification and Implants

CONFIDENTIAL 61
Device Evolution – History in Spine
Development Paradigm → Form, Fit, and Function
(Cause and Effect = Iteration)
Cylindrical Cages (1994) PEEK/Carbon Fiber (1999) PEEK (2003)
Williams et. Al., American Journal of Neuroradiology September 2005, 26 (8) 2057-2066
Walsh, WR, et al., The Spine Journal, 15:5, 2015, 1041-1049

CONFIDENTIAL 62
Device Evolution – Function and Biologics
Development Paradigm → Form, Fit, and Function
+ Bulk Material + Surface Modification (Biological Interaction)
Williams et. Al., American Journal of Neuroradiology September 2005, 26 (8) 2057-2066
Titanium Modified (2008) Composite PEEK (2012) 3D Printed (2014)

CONFIDENTIAL 63
New Design Paradigm
• Bulk Mechanical Properties
• Nano-structured implants
resemble natural tissues, and
provide more control over
biological interactions
• Types of surface modification
– Micro/Nano-fabrication (e.g. lithography)
– Mechanical (e.g. shot peening)
– Subtractive (e.g. etching)
– Additive (e.g. coating)
Today’s Implant
0
6
6
4
2
0
4
2
0
microns
microns
6microns
1.3
0
6
4
2
0
microns
6
4
2
0microns
0
1.3
microns
Nano-structured
Implant
T. J. Webster, in Advances in Chemical Engineering Vol. 27, Academic Press, NY, pgs. 125-166, 2001.

CONFIDENTIAL 64
Biomaterial Interactions In Vivo
• Biomaterials introduced into the body are immediately
surrounded by a protein corona
• Proteins respond to stimuli at the nano-scale
• The specific proteins that attach depend on the surface
properties of the material (energy, roughness, chemistry)
T. J. Webster, Nanotek Expo, 2013

CONFIDENTIAL 65
Nature and Polymers - Nano-Fabrication
The pillared nanostructure of cicada wings is inherently
antimicrobial (regardless of surface chemistry)1
1. Ivanova et al., Small, 2012
2. Pogodin et al. Biophys. J. 2013, 104, 835-840.
3. Dickson et al. Biointerphases. 2015, 10, 021010.
E. Coli on flat PMMA (left) and nanopillared PMMA (right),
fabricated using nanoimprint lithography3

CONFIDENTIAL 66
Stainless Steel - Mechanical
Bagherifard, S, Hickey, DJ, et al., Biomaterials, 2015, 185-197.
Not peened Conventionally shot peened Severely shot peened
The shot peening process mechanically modified the surface energy and roughness.
These parameters directly influenced cell and bacteria interactions.
The expression of vinculin focal adhesion contacts from
osteoblasts was directly related to surface energy
Bacterial colonization was inversely related to
nanoscale surface roughness

CONFIDENTIAL 67
Titanium - Subtractive
Images courtesy of T. J. Webster
Rat amputee model1 μm1 μm
Unmodified Ti Anodized Ti
Rat walking on anodized Ti implant
3 days after surgery
Unmodified Ti
Lack of bone growth
Anodized Ti
Excellent bone growth
28 days
post-implantation
No infection

CONFIDENTIAL 68
Composites - Additive
Ti-Bond PEEK
4 weeks
12 weeks
Bone contact = 64.5% Bone contact = 21.3%
Bone contact = 70.0% Bone contact = 20.5%

CONFIDENTIAL 69
BioTy®- Controllable Antibacterial Efficacy
0
0.5
1
1.5
2
Control 0.1%,
20V,
60s
0.5%,
20V,
30s
0.5%,
20V,
75s
0.5%,
20V,
120s
0.5%,
80V,
30s
0.5%,
80V,
120s
0.5%,
150V,
60s
0.5%,
150V,
90s
1.0%,
150V,
90s
S.aureusColonization
Colonization of Staphylococcus aureus after 4 hrs of culture on the indicated sample groups.
Data represent the Avg ± StDev.
Increasing coating thickness

CONFIDENTIAL 70
Key Takeaways
• New Product Development Paradigm
– Design (Form, Fit, Function);
– Material Selection;
– Surface Modification
• Special focus should be given to the resulting
nanostructure, as proteins operate at this scale
and influence different cell attachment.
• Different modification approaches exists
depending on the substrate material.

2 | Public | June 14, 2017 | OMTEC Presentation | Balaji Prabhu
.

3
2016: Evonik in figures
| Public | June 14, 2017 | OMTEC Presentation | Balaji Prabhu

4
2016: Evonik in figures

5
Evonik Favors a Decentralized R&D Approach

6
Evonik Favors a Decentralized R&D Approach
Evonik Venture Capital
(€100 million over the medium
term)
Expansion
of Existing
Businesses
~90%
Establishment of new
businesses, competence
platforms
~10%
Business Segments
 Focus on existing markets & technologies
 Strong customer orientation
 Short-term & medium-term projects
Strategic Innovation Unit - Creavis
 Focus on new business options and new
competence platforms
 Medium-term & long-term projects
Direct Investments
 Nanocomp, Biosynthetic Technologies, Algal
Scientific, Wiivv, JeNaCell
algae-based omega-3 fatty acid product for use in animal feeds.
FAVOR® superabsorbent polymer used in diapers
Plexiglas - Poly(methyl methacrylate)

7
Evonik Polymers Currently used in Medical Applications
www.evonik.com/medical
VESTAKEEP® PEEK Applications:
Spine, sports medicine, trauma, CMF, cardiovascular, drug ports,
dental, medical textiles, ophthalmic, surgical instruments, housings.

8
Medical Application primary support sites

9
Existing and New Material : Questions
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New Material Development: “Pull vs Push”
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Design & Development: “New Materials Technology”
Design Control Guidance For Medical Device Manufacturers
https://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm070627.htm
Medical Devices OEM Process

12

13

14
FeedbackDeliveryFinalizationPlanning EvaluationSelection
Some Best Practices for efficient OEM – Supplier synergy
• Material choice
• Risks & controls
• Market publicity
• Showcase new
materials
• Supplier capabilities
• Supplier competencies
• OEM open-houses
• Onsite visits
• Recovery/Control Plans
• Traceability
• In-house
Quality Team
• Supplier Quality
Plan
• Internal & External
Standards
• Agreement
• Supplier Quality
Agreement
• ISO 13485 conformity
• Volume & Forecast
• COPQ
• Continuity Plans
• Change Management
• Periodic Audit
• CAPA
• Audit Support
• Continuous
improvement
OEMSupplier
Partnership &
Collaboration
Risk v. Reward
Market Potential
& Growth
Adaptation
Timeline / Cost
Quality
Conformance &
Excellence
Process
Excellence
Synergy

15
Material Supplier to “Solution Provider”

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Material Supplier to “Solution Provider”

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Absorbable Metals Advancements

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