Innovation in orthopaedics is linked to the adoption of new materials and new manufacturing processes for established materials. This rapid-fire presentation profiles the properties, indications and manufacturing processes that advance the use of different materials.
Individual topics that will be covered include: Polymers: R&D support, Bio-absorbable metals, Modified implant surfaces and Titanium Injection Molding
Rapid Fire: Raw Materials Advancements - OMTEC 2017
1.
2. Adam Griebel
R&D, Fort Wayne Metals
Absorbable Metals
OMTEC 2017 – Raw Material Advancements
3. 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.
10. 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.
15. Magnesium: the best bet
T Kraus et al. / Acta Biomaterialia 8 (2012) 1230-1238
• Ø1.6 mm pins
• Rat femur
• 24 weeks
16. 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
17. Mg screws in the clinic
Biber, Trauma Case
Reports, 201717 months6 weeks
• Syntellix
• CE Marking for Magnezix® compression screw in 2013
18. Mg screws in the clinic
Pre-op T = 0 T = 6 mo T = 1 yr
Lee et al, PNAS 113 (2016) 716-721
26. 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
27. Alloy Example: Resoloy®
• Mg-Rare Earth alloy (vascular indication)
Resoloy® is a registered trademark of MeKo, Sarstedt, Germany
28. Alloy Example: Resoloy®
• Mg-Rare Earth alloy (vascular indication)
Resoloy® is a registered trademark of MeKo, Sarstedt, Germany
29. Alloy Example: Resoloy®
• Mg-Rare Earth alloy (vascular indication)
Resoloy® is a registered trademark of MeKo, Sarstedt, Germany
30. Alloy Example: Resoloy®
• Mg-Rare Earth alloy (vascular indication)
Resoloy® is a registered trademark of MeKo, Sarstedt, Germany
31. Alloy Example: Resoloy®
• Mg-Rare Earth alloy (vascular indication)
Resoloy® is a registered trademark of MeKo, Sarstedt, Germany
32. Alloy Example: Resoloy®
• Mg-Rare Earth alloy (vascular indication)
Resoloy® is a registered trademark of MeKo, Sarstedt, Germany
33. Alloy Example: Resoloy®
• Mg-Rare Earth alloy (vascular indication)
Resoloy® is a registered trademark of MeKo, Sarstedt, Germany
34. Alloy Example: Resoloy®
• Mg-Rare Earth alloy (vascular indication)
Resoloy® is a registered trademark of MeKo, Sarstedt, Germany
35. Alloy Example: Resoloy®
• Mg-Rare Earth alloy (vascular indication)
Resoloy® is a registered trademark of MeKo, Sarstedt, Germany
36. Alloy Example: Resoloy®
• Mg-Rare Earth alloy (vascular indication)
Resoloy® is a registered trademark of MeKo, Sarstedt, Germany
37. 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
38. Future Directions
• Continue towards commercial scale
• Cold-work impact on corrosion
• Influence of coatings & surface modifications
• Device-specific property tuning
39. In Summary
• Absorbable metals can offer real benefits
• Magnesium is most promising for
orthopedic applications
• Inquiries: adam_griebel@fwmetals.com
41. 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
43. 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
44. 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
45. 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
46. 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
47. ‘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
49. 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
51. 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
52. 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
53. 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
54. 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
55. 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
56. 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
57. 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
58. 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
59. Thank you
OMTEC 2017
Jobe Piemme
Vice President, Business Development
Praxis Technology
jpiemme@praxisti.com
518-812-0112
60. Jeff Tyber, MS: CEO/President
Dan Hickey, PhD: Postdoctoral Scientist
Providing Rapid Access to Portfolio Enhancing, Regulatory Approved, Orthopedic Implants
Surface Modification and Implants
61. 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
62. 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
Walsh, WR, et al., The Spine Journal, 15:5, 2015, 1041-1049
Titanium Modified (2008) Composite PEEK (2012) 3D Printed (2014)
63. 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.
64. 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
65. 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
66. 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
67. 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
68. CONFIDENTIAL 68
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%
69. 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
70. 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.
72. 2 | Public | June 14, 2017 | OMTEC Presentation | Balaji Prabhu
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73. 3
2016: Evonik in figures
| Public | June 14, 2017 | OMTEC Presentation | Balaji Prabhu
74. 4
2016: Evonik in figures
| Public | June 14, 2017 | OMTEC Presentation | Balaji Prabhu
75. 5
Evonik Favors a Decentralized R&D Approach
| Public | June 14, 2017 | OMTEC Presentation | Balaji Prabhu
76. 6
Evonik Favors a Decentralized R&D Approach
Evonik Venture Capital
(€100 million over the medium
term)
| Public | June 14, 2017 | OMTEC Presentation | Balaji Prabhu
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)
77. 7
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.
81. 11
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
Medical Devices OEM Process
82. 12
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
83. 13
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
84. 14
FeedbackDeliveryFinalizationPlanning EvaluationSelection
Some 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 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
85. 15
Material Supplier to “Solution Provider”
| Public | June 14, 2017 | OMTEC Presentation | Balaji Prabhu
86. 16
Material Supplier to “Solution Provider”
| Public | June 14, 2017 | OMTEC Presentation | Balaji Prabhu
87. 17
| Public | June 14, 2017 | OMTEC Presentation | Balaji Prabhu