rapid fire: raw materials advancements - omtec 2017
TRANSCRIPT
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
What are Absorbable Metals?
Nutrient Metals
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
Mg screws in the clinic
Biber, Trauma Case Reports, 2017 17 months 6 weeks
• Syntellix • CE Marking for Magnezix® compression screw in 2013
Mg screws in the clinic
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)
Primary considerations • Mechanical
– Strength (lower) – Ductility (lower)
Primary considerations • 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
Primary considerations • 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
Primary considerations • 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)
Resoloy® is a registered trademark of MeKo, Sarstedt, Germany
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)
Resoloy® is a registered trademark of MeKo, Sarstedt, Germany
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)
Resoloy® is a registered trademark of MeKo, Sarstedt, Germany
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)
Resoloy® is a registered trademark of MeKo, Sarstedt, Germany
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)
Resoloy® is a registered trademark of MeKo, Sarstedt, Germany
Alloy Example: Resoloy® • Mg-Rare Earth alloy (vascular indication)
0
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0 10 20 30 40 50di
ssol
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Mg2+
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500°C450°C400°C50% CW350°C250°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: [email protected]
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
Markets
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
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
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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
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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 Walsh, WR, et al., The Spine Journal, 15:5, 2015, 1041-1049
Titanium Modified (2008) Composite PEEK (2012) 3D Printed (2014)
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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
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Nano-structured Implant
T. J. Webster, in Advances in Chemical Engineering Vol. 27, Academic Press, NY, pgs. 125-166, 2001.
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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
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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
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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
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Titanium - Subtractive
Images courtesy of T. J. Webster
Rat amputee model 1 μm 1 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
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Composites - Additive
Walsh, WR, et al., The Spine Journal, 15:5, 2015, 1041-1049
Ti-Bond PEEK
4 weeks
12 weeks
Bone contact = 64.5% Bone contact = 21.3%
Bone contact = 70.0% Bone contact = 20.5%
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BioTy®- Controllable Antibacterial Efficacy
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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. a
ureu
s Col
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Colonization of Staphylococcus aureus after 4 hrs of culture on the indicated sample groups. Data represent the Avg ± StDev.
Increasing coating thickness
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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.
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2016: Evonik in figures
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2016: Evonik in figures
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Evonik Favors a Decentralized R&D Approach
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Evonik Favors a Decentralized R&D Approach
Evonik Venture Capital(€100 million over the medium
term)
| Public | June 14, 2017 | OMTEC Presentation | Balaji Prabhu
Expansionof ExistingBusinesses
~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)
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Evonik Polymers Currently used in Medical Applications
www.evonik.com/medical| Public | June 14, 2017 | OMTEC Presentation | Balaji Prabhu
VESTAKEEP® PEEK Applications: Spine, sports medicine, trauma, CMF, cardiovascular, drug ports, dental, medical textiles, ophthalmic, surgical instruments, housings.
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Medical Application primary support sites
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Existing and New Material : Questions
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New Material Development: “Pull vs Push”
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Design & Development: “New Materials Technology”
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Design Control Guidance For Medical Device Manufacturers
https://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm070627.htm
Medical Devices OEM Process
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Design & Development: “New Materials Technology”
| Public | June 14, 2017 | OMTEC Presentation | Balaji Prabhu
Design Control Guidance For Medical Device Manufacturers
https://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm070627.htm
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Design & Development: “New Materials Technology”
| Public | June 14, 2017 | OMTEC Presentation | Balaji Prabhu
Design Control Guidance For Medical Device Manufacturers
https://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm070627.htm
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FeedbackDeliveryFinalizationPlanning EvaluationSelectionSome Best Practices for efficient OEM – Supplier synergy
| Public | June 14, 2017 | OMTEC Presentation | Balaji Prabhu
• 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 QualityPlan
• Internal & External Standards
• Agreement
• Supplier Quality Agreement
• ISO 13485 conformity
• Volume & Forecast
• COPQ
• Continuity Plans
• Change Management
• Periodic Audit
• CAPA
• Audit Support
• Continuous improvement
OE
MS
uppl
ier
Partnership & CollaborationRisk v. Reward Market Potential
& GrowthAdaptation
Timeline / Cost
Quality Conformance &
Excellence
Process ExcellenceS
yner
gy
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Material Supplier to “Solution Provider”
| Public | June 14, 2017 | OMTEC Presentation | Balaji Prabhu
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Material Supplier to “Solution Provider”
| Public | June 14, 2017 | OMTEC Presentation | Balaji Prabhu
17| Public | June 14, 2017 | OMTEC Presentation | Balaji Prabhu
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