Rapid Fire: Raw Materials Advancements - OMTEC 2017

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.

4. Why do we want Absorbable Metals?

5. 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

6. 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

7. What are Absorbable Metals?

8. Nutrient Metals

9. 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

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.

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

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

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

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

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

19. Designing with Magnesium What is important to consider?

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

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

22. 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

23. 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

24. Primary considerations • Mechanical • Corrosion • Biological • Intellectual – Crowded IP landscape

25. Magnesium Development at Fort Wayne Metals

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

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

40. Biocompatibility of Titanium MIM

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

42. Markets 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

48. 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

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

50. Guidance – ISO 10993 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 .

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.

78. 8 Medical Application primary support sites | Public | June 14, 2017 | OMTEC Presentation | Balaji Prabhu

79. 9 Existing and New Material : Questions | Public | June 14, 2017 | OMTEC Presentation | Balaji Prabhu                                       

80. 10 New Material Development: “Pull vs Push”              

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

88. CONFIDENTIAL 71

Rapid Fire: Raw Materials Advancements - OMTEC 2017

Rapid Fire: Raw Materials Advancements - OMTEC 2017

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