rapid fire: raw materials advancements - omtec 2017

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

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, 2017 17 months 6 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)

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

0 10 20 30 40 50di

2 ]time (h)

500°C450°C400°C50% CW350°C250°C

t = 0 hrs

t = 45 hrs

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

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

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 Walsh, WR, et al., The Spine Journal, 15:5, 2015, 1041-1049

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

6 4 2 0

0 microns

microns

6 microns 1.3 0

microns 6 4 2 0 microns

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 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

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%

CONFIDENTIAL 69

BioTy®- Controllable Antibacterial Efficacy

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,

1.0%,150V,

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

2016: Evonik in figures

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

2016: Evonik in figures

Evonik Favors a Decentralized R&D Approach

Evonik Venture Capital(€100 million over the medium

Expansionof ExistingBusinesses

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)

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.

Medical Application primary support sites

Existing and New Material : Questions

New Material Development: “Pull vs Push”

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

FeedbackDeliveryFinalizationPlanning EvaluationSelectionSome 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 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

Partnership & CollaborationRisk v. Reward Market Potential

& GrowthAdaptation

Timeline / Cost

Quality Conformance &

Excellence

Process ExcellenceS

Material Supplier to “Solution Provider”

17| Public | June 14, 2017 | OMTEC Presentation | Balaji Prabhu

CONFIDENTIAL 71

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