Advances in Biomaterials THE STORY OF SILICON NITRIDEcontent.stockpr.com/amedica/db/265/946/pdf/Executive+Summary+12.13... · Advances in Biomaterials . THE STORY OF SILICON NITRIDE

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Advances in Biomaterials

THE STORY OF SILICON NITRIDEA Brief Narrative - By Amedica Corporation

Introduction:

At Amedica Corporation, we make and develop silicon nitride ceramics particularly for biomedical applications. This summary will share our knowledge, passion, and experience with you.

What is silicon nitride (Si3N4)?Silicon nitride is an inorganic and non-metallic compound, made of silicon and nitrogen, two elements that are critical to life.1–4 Discovered in 1857, silicon nitride remained a scientific curiosity until commercial applications began in the 1950’s.5

The U.S. and Japanese governments funded ceramics engineering research that addressed silicon nitride manufacturing costs were reduced 1970’s-1980’s. As a result, silicon nitride was adopted quickly in many industries.6 In the 1990’s, naturally occurring silicon nitride was found in meteorite stardust, suggesting intergalactic origins from the beginning of time.7

Properties:Silicon nitride is a ceramic.To make it, selected material powders are mixed into slurry, that is molded into desired shapes. Those shapes are then crafted, and finished in high-temperature and -pressure furnaces. This is similar to akin to making pottery; the word “ceramic” comes from the Greek root “kéramos” that refers to pottery.8

Silicon nitride is extremely strong and reliable resisting abrasion, corrosion, heat and chemical attack. It has the highest fracture resistance of any advanced ceramic.9 These properties have led to widespread application

in many industries.

Industrial Uses:

Today, silicon nitride is found in high-end bearings for gas and diesel engines, wind turbines, motorsports equipment, bicycles, rollerblades, skateboards, computer disk drives, machine tools, dental hand-pieces, and flap-actuators in aircraft.10 Wherever corrosion, rapid wear, and electric or magnetic fields limit


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the use of metals, silicon nitride is used instead.7, 11, 12 As an example, silicon nitride is used to make the bearings of underwater ocean tidal flow meters, where severe seawater corrosion limits other materials.13

Because of its extreme strength, hardness, and resistance to chemical and thermal factors,11, 12, 14–16 silicon nitride is commonly used in high-speed cutting tools, and to break up rocks during oil fracking.17 Its heat resistance has led to uses in the valve trains of gas-18 and diesel-engines,11 rotors and stators in gas-turbines,19, 20 automotive turbochargers,21 and rocket nozzles and thrusters.22 Few materials can survive under these extreme conditions.

Outer Space:Silicon nitride is used in space applications. It is in the cryogenic pump bearings of NASA space shuttles,23 the thrusters of the Japanese space probe, Akatsuki,24 and provides a lifespan of >10,000,000 years of space travel to tungsten-etched memory chips for spacecraft.25

Medical Implants:Amedica Corporation makes implants for spinal fusion surgery from medical-grade silicon nitride. These implants can be dense, porous, or a combination of dense-porous to mimic the cortical-cancellous structure of living bone.26, 27 Silicon nitride is very biocompatible and bioactive, has bacterial resistance, and shows excellent bone affinity.28 With >30,000 spine implantations spanning almost 10 years and no reported failures, Amedica markets its products with confidence.29


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Additionally, silicon nitride can be polished to provide a smooth and wear-resistant surface for articulating applications, such as bearings for hip and knee replacements.30–32 The proven benefits of silicon nitride include all of the following properties:

� material phase stability33

� wear resistance33, 34

� strength and fracture toughness9

� hydrophilicity35

� favorable imaging36

� bacterial resistance37, 69, 72

The Evolution of Biomaterials:Historically, materials such as wood, leather, pig bladders, glass, and ivory were used for orthopaedic reconstructive surgery such as repairing broken hips, and treating hip arthritis.38 Today, metals, bone grafts, and polymers are used to rebuild our skeleton, and help maintain function into old age.

All biomaterials degrade in the wet, warm, saline environment of the human body - metals fret and corrode,39 plastics oxidize,40 and allograft bone never fully heals,41 all of which lead to long-term failures. Today, for example, toxic wear from all-metal hip bearings is a well-known problem;42 and fretting and electrochemical corrosion in total hips is an emerging concern.43

Silicon nitride can address these concerns. Not only is its wear extremely low,44 but the minimal wear particles are soluble and can be cleared from the body.45 Silicon nitride is also chemically resistant, hard, stiff, and has a high dielectric constant, all of which discourage fretting and corrosion.46

Plastic (polyethylene) bearings in artificial hip and knee joints oxidize over time, leading to strategies such as cross-linking47 and vitamin E doping48 to slow down this process. Silicon nitride’s unique surface chemistry actually absorbs oxygen from polyethylene,44, 49 thus limiting polyethylene oxidation in hip and knee replacements.

Bone grafts present significant limitations due to harvesting morbidity, lack of bioactivity, and concerns about disease transmission.41 Synthetic bone fillers are made from a material called hydroxyapatite, which has an affinity for bone but is still very brittle.50–52 Silicon nitride bone scaffolds and bone-fusion devices53 provide superior and reliable mechanical strength, with bone healing similar to hydroxyapatite.54

On X-ray images, plastic implants are invisible while metals obscure visibility of bone anatomy behind the implant. CT scans and MRI scans are also distorted by metal implants. In contrast, silicon nitride is easily seen on X-rays, does not block imaging of bone anatomy behind the implant, and its dielectric and non-magnetic nature eliminates distortion in CT and MRI scans.36

In sum, silicon nitride has the right combination of strength, toughness, wear resistance, biocompatibility, bioactivity, bone integration, structural stability, corrosion resistance, and easier imaging, all of which are desirable in medical implants.55

Image courtesy of W. M. Rambo, Jr., M.D.


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Other Bioceramics:Ceramics such as alumina (Al2O3) and zirconia (ZrO2) have been used in hip and knee replacements because of less wear than metal surfaces.56–58 Alumina is brittle; it can break suddenly.59 Zirconia is stronger, but can degrade after implantation, leading to erratic outcomes.60 In 2002, zirconia was withdrawn after a number of failures from uncontrolled material transformation.61

A mix of alumina and zirconia, called zirconia-toughened alumina (ZTA) is a popular ceramic used in hip and knee implants.62 ZTA is an engineering compromise between the alumina and zirconia.63 While improved over zirconia, ZTA can still degrade in the body, therby reducing its surface mechanical integrity.64

When used in hip and knee replacements, alumina and ZTA both release oxygen ions, which can degrade polyethylene bearings.49, 65 In contrast, silicon nitride is a non-oxide ceramic, that is not only stronger and tougher than alumina and ZTA,9 but also removes oxygen from polyethylene.66, 67 This remarkable property could support hip and knee replacements well beyond two decades of service, something that is only a speculation today.

Scientific & Clinical Data:Aside from superior strength, wear resistance, corrosion resistance, and fracture toughness,68 there is more to silicon nitride. Our scientific findings are summarized below:

Bone Healing: Silicon nitride turns on osteoblasts (bone-forming cells) and suppresses osteoclasts (bone absorbing cells). A manufacturing change called “nitrogen-annealing” results in a near-200% increase in bone formation by cells exposed to silicon nitride.54 This finding has excellent implications for speeding up bone healing, bone fusion, and implant ingrowth into the skeleton.

Supporting superior bone healing is the finind that living cells adhere preferentially to silicon nitride over polymer or metal.69 Cell adhesion promotes tissue development, and enhances the bioactivity of materials. Cell adhesion to silicon nitride is a function of pH, chemical, and ionic changes at the material surface.

Composite Devices: In a clinical trial, a spine interbody device made of both solid and porous silicon nitride fused the cervical spine without added cells or bone fillers.70 Composite devices based on porous silicon nitride herald a new class of reconstructive implants.27, 71

Impr

ovem

ent o

n A

I 2O3

(%) 50

40

30

20

10

0As+sintered

SI3N4

HF-etchedSI3N4

OxidizedSI3N4

N2+annealedSI3N4

Cell Proliferation Test

Impr

ovem

ent o

n A

I 2O3

(%) 250

200

150

100

50

0As+sintered

SI3N4

HF-etchedSI3N4

OxidizedSI3N4

N2+annealedSI3N4

Osteoconductivity Test

+ 40% increase incell proliferation upon

nitrogen annealing

+ 190% increase inosteoconductivity upon

nitrogen annealing


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Infection Prevention: Bacterial infection of any biomaterial implant is a serious risk. Solutions have included material coatings, surface texturing, antibiotic treatments, and other enhancements to confer bacterial resistance. Silicon nitride offers an easy solution; not only is it is inherently resistant to bacteria and biofilm formation,37, 69 recent studies have shown direct bactericidal effect against oral bacteria.72

As with cell adhesion, the antibacterial behavior of silicon nitride relates to its complex surface phenomena invoking chemistry, surface pH, texture, and electrical charge properties.35 The surface modulation of silicon nitride to optimize the desired properties for specific implants, is a clear advantage of the material.35

The Future:With an expanding, ageing, and more active world population, materials like silicon nitride will lead improved biomedical implant safety, high-performance, and lifetime durability. Others agree; see for example- the title of a recent peer review article concerning silicon nitride below. .

CFU

/m

m3

(Log

base

10

scal

e)

1.E+07

1.E+06

1.E+05

1.E+04

1.E+03

1.E+02

1.E+01

1.E+00

1.E+07

1.E+06

1.E+05

1.E+04

1.E+03

1.E+02

1.E+01

1.E+0024 Hours 48 Hours 24 Hours 48 Hours

S epidermidis on Biomaterials

CFU

/m

m3

(Log

base

10

scal

e)

E coli on Biomaterials

PEEK Titanium Silicone Nitride PEEK Titanium Silicone Nitride

Silicon nitride demonstrates superior resistance to E coli and S epidermidisbiofilm formation relative to other commercial biomaterials.


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References:1 R. Jugdaohsingh, “Silicon and Bone Health,” J Nutr Heal. Aging, 11 [2] 99–110 (2007).

2 L.M. Jurkic, I. Cepanec, S.K. Pavelic, and K. Pavelic, “Biological and Therapeutic Effects of Ortho-Silicic Acid and some Ortho-Silicic Acid-Releasing Compounds: New Perspectives for Therapy,” Nutr. Metab. (Lond)., 10 [1] 2 (2013).

3 D.M. Reffitt, N. Ogston, R. Jugdaohsingh, H.F.J. Cheung, B.A.J. Evans, R.P.H. Thompson, J.J. Powell, and G.N. Hampson, “Orthosilicic Acid Stimulates Collagen Type 1 Synthesis and Osteoblastic Differentiation in Human Osteoblast-Like Cells in vitro,” Bone, 32 [2] 127–135 (2003).

4 M. Schneider, “The Importance of Ammonia in Mammalian Cell Culture,” J. Biotechnol., 46 [3] 161–185 (1996).

5 R.C. Sangster and D.J. Fisher, “Part C. Si3N4 Products, Uses and Markets;” pp. 137–246 in Form. Silicon Nitride from 19th to 21st Century, 2nd ed. Geneva, Switzerland, 2015.

6 A.J. Fyzik and D.R. Beamant, “Microstructure and Properties of Self-Reinforced Silicon Nitride,” J. Am. Ceram. Soc., 76 [11] 2737–2744 (1993).

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18 B.J. McEntire, R.W. Wills, and R.E. Southam, The Development and Testing of Ceramic Components in Piston Engines, Final Report, Prepared for the U.S. Department of Energy under Contract with Oak Ridge National Laboratories, Contract No. DE-AC05-840R21400. Oak Ridge, TN 37831-6285, 1994.

19 W.D. Carruthers, P.F. Becher, M.K. Ferber, and J. Pollinger, “Advances in the Development of Silicon Nitride and Other Ceramics;” pp. 1–10 in Proc. ASME Turbo Expo 2002. Amsterdam, The Netherlands, 2002.

20 B.J. McEntire, R.R. Hengst, W.T. Collins, A.P. Taglialavore, and R.L. Yeckley, “Ceramic Component Processing Development for Advanced Gas Turbine Engines,” J. Eng. Gas Turbines Power, 115 [1] 1–8 (1993).

21 T. Shimizu, K. Takama, H. Enokishima, K. Mikame, S. Tsuji, and N. Kamiya, “Silicon Nitride Turbocharger Rotor for High Performance Automotive Engines,” SAE Tech. Pap., No. 900656 (1990).

22 A.J. Eckel, “Silicon Nitride Rocket Thrusters Test Fired Successfully,” NASA Res. News, https://web.archive.org/web/20090404161958/http:// (2009).

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24 N. Kawai, K. Tsurui, D. Shindo, Y. Motoyashiki, and E. Sato, “Fracture Behavior of Silicon Nitride Ceramics Subjected to Hypervelocity Impact,” Int. J. Impact Eng., 38 [7] 542–545 (2011).

25 J. De Vries, D. Schellenberg, and L. Abelmann, “Towards Gigayear Storage Using a Silicon-Nitride/Tungsten Based Medium,” Cornell Univ. arXiv1310.2961v1 [cs.ET] 9, [October 2013] 1–19 (2013).

26 K. Bodišová, M. Kašiarová, M. Domanická, M. Hnatko, Z. Lencéš, Z.V. Nováková, J. Vojtaššák, S. Gromošová, et al., “Porous Silicon Nitride Ceramics Designed for Bone Substitute Applications,” Ceram. Int., 39 [7] 8355–8362 (2013).

27 K.S. Ely, A.C. Khandkar, R. Lakshminarayanan, and A.A. Hofmann, “Hip Prosthesis with Monoblock Ceramic Acetabular cup,” US Pat. 8,133,284, (2012).

28 T.J. Webster, A.A. Patel, M.N. Rahaman, and B.S. Bal, “Anti-Infective and Osteointegration Properties of Silicon Nitride, Poly (Ether Ether Ketone), and Titanium Implants,” Acta Biomater., 8 [12] 4447–4454 (2012).

29 Personal Communication from William Jordan, Director of Regulatory Affairs and Quality Assurance, Amedica Corporation, Salt Lake City, UT 84119, (2014).

30 Y.S. Zhou, M. Ohashi, N. Tomita, K. Ikeuchi, and K. Takashima, “Study on the Possibility of Silicon Nitride—Silicon Nitride as a Material for Hip Prostheses,” Mater. Sci. Eng. C, 5 125–129 (1997).

31 M. Mazzocchi, D. Gardini, P.L. Traverso, M.G. Faga, and A. Bellosi, “On the Possibility of Silicon Nitride as a Ceramic for Structural Orthopaedic Implants. Part II: Chemical Stability and Wear Resistance in Body Environment,” J. Mater. Sci. Mater. Med., 19 2889–2901 (2008).

32 M. Mazzocchi and A. Bellosi, “On the Possibility of Silicon Nitride as a Ceramic for Structural Orthopaedic Implants. Part I: Processing, Microstructure, Mechanical Properties, Cytotoxicity,” J. Mater. Sci. Mater. Med., 19 2881–2887 (2008).

33 B.S. Bal, A. Khandkar, R. Lakshminarayanan, I. Clarke, A.A. Hofmann, and M.N. Rahaman, “Testing of Silicon Nitride Ceramic Bearings for Total Hip Arthroplasty,” J. Biomed. Mater. Res. Part B Appl. Biomater., 87 [2] 447–454 (2008).

34 B.J. McEntire, B.S. Bal, A. Lakshminarayanan, and R. Bock, “Silicon Nitide Bearings for Total Joint Arthroplasty,” Bone Jt. J, 98-B [SUPP 1] 34 (2016).

35 R.M. Bock, B.J. McEntire, B.S. Bal, M.N. Rahaman, M. Boffelli, and G. Pezzotti, “Surface Modulation of Silicon Nitride Ceramics for Orthopaedic Applications,” Acta Biomater., 26 318–330 (2015).

36 M. Anderson, J. Bernero, and D. Brodke, “Medical Imaging Characteristics of Silicon Nitride Ceramic A New Material for Spinal Arthroplasty Implants;” p. 547 in 8th Annu. Spine Arthroplast. Soc. Glob. Symp. Motion Preserv. Technol. Miami, FL, 2008.

37 D.J. Gorth, S. Puckett, B. Ercan, T.J. Webster, M. Rahaman, and B.S. Bal, “Decreased Bacteria Activity on Si3N4 Surfaces Compared with PEEK or Titanium,” Int. J. Nanomedicine, 7 4829–4840 (2012).

38 D.R. Steinberg and M.E. Steinberg, “The Early History of Arthroplasty in the United States,” Clin. Orthop. Relat. Res., 374 55–89 (2000).

39 D. Sun, J.A. Wharton, and R.J.W. Wood, “The Effects of Proteins and pH on Tribo-Corrosion Performance of Cast CoCrMo: A Combined Electrochemical and Tribological Study,” Tribol. Surfaces Interfaces, 2 [3] 150–160 (2008).

40 S.L. Rowell, C.R. Reyes, H. Malchau, and O.K. Muratoglu, “In Vivo Oxidative Stability Changes of Highly Cross-Linked Polyethylene Bearings: An Ex Vivo Investigation,” J. Arthroplasty, 30 1828–1834 (2015).


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41 A.S. Brydone, D. Meek, and S. Maclaine, “Bone Grafting, Orthopaedic Biomaterials, and the Clinical Need for Bone Engineering,” Proc. Inst. Mech. Eng. Part H J. Eng. Med., 224 [12] 1329–1343 (2010).

42 J.S. Melvin, T. Karthikeyan, R. Cope, and T.K. Fehring, “Early Failures in Total Hip Arthroplasty - A Changing Paradigm,” J. Arthroplasty, 29 [6] 1285–1288 (2014).

43 H.J. Cooper, R.M. Urban, R.L. Wixson, R.M. Meneghini, and J.J. Jacobs, “Adverse local tissue reaction arising from corrosion at the femoral neck-body junction in a dual-taper stem with a cobalt-chromium modular neck.,” J. Bone Joint Surg. Am., 95 [10] 865–72 (2013).

44 R.C. Dante and C.K. Kajdas, “A Review and a Fundamental Theory of Silicon Nitride Tribochemistry,” Wear, 288 27–38 (2012).

45 J. Olofsson, T. Grehk, and T. Berlind, “Evaluation of Silicon Nitride as a Wear Resistant and Resorbable Alternative for Total Hip Joint Replacement,” Biomatter, 2 [2] 94–102 (2012).

46 M. Pettersson, A. Oladokun, M. Bryant, H. Engqvist, and C. Persson, “Fretting Corrosion of Silicon Nitride against Cobalt Chromium and Titanium Medical Alloys;” p. Poster 0951 in Proc. Orthop. Res. Soc. 2015.

47 G. Lewis, “Properties of Crosslinked Ultra-High-Molecular-Weight Polyethylene,” Biomaterials, 22 [4] 371–401 (2001).

48 A. Turner, Y. Okubo, S. Teramura, Y. Niwa, K. Ibaraki, T. Kawasaki, D. Hamada, K. Uetsuki, et al., “The Antioxidant and Non-Antioxidant Contributions of Vitamin E in Vitamin E Blended Ultra-High Molecular Weight Polyethylene for Total Knee Replacement,” J. Mech. Behav. Biomed. Mater., 31 21–30 (2014).

49 G. Pezzotti, “Bioceramics for Hip Joints: The Physical Chemistry Viewpoint,” Materials (Basel)., 7 4367–4410 (2014).

50 L. Sun, C.C. Berndt, K.A. Gross, and A. Kucuk, “Material Fundamentals and Clinical Performance of Plasma-Sprayed Hydroxyapatite Coatings: A Review,” J. Biomed. Mater. Res. Appl. Biomater., 58 570–592 (2001).

51 A.A. Chaudhry, H. Yan, K. Gong, F. Inam, G. Viola, M.J. Reece, J.B.M. Goodall, I. ur Rehman, et al., “High-Strength Nanograined and Translucent Hydroxyapatite Monoliths via Continuous Hydrothermal Synthesis and Optimized Spark Plasma Sintering,” Acta Biomater., 7 [2] 791–799 (2011).

52 H. Yoshikawa and A. Myoui, “Bone tissue engineering with porous hydroxyapatite ceramics,” J. Artif. Organs, 8 [3] 131–136 (2005).

53 M.C. Anderson and R. Olsen, “Bone Ingrowth into Porous Silicon Nitride,” J. Biomed. Mater. Res., 92A 1598–1605 (2010).

54 G. Pezzotti, B.J. McEntire, R.M. Bock, M. Boffelli, W.-L. Zhu, E. Vitale, L. Puppulin, T. Adachi, et al., “Silicon Nitride: A Synthetic Mineral for Vertebrate Biology,” Sci. Rep., (in press) (2016).

55 B.S. Bal and M. Rahaman, “The Rationale for Silicon Nitride Bearings in Orthopaedic Applications;” pp. 421–432 in Adv. Ceram. - Electr. Magn. Ceram. Bioceram. Ceram. Environ. INTEC Open Access Publisher, 2011.

56 R. Tsukamoto, S. Chen, H. Shoji, and I.C. Clarke, “Improved Wear Performance with Crosslinked UHMWPE and Zirconia Implants in Knee Simulation;” p. 1686 in Proc. 51st Annu. Meet. Orthop. Res. Soc. Orthopaedic Research Society, Washington, DC USA, 2005.

57 S. Williams, M. Butterfield, T. Stewart, E. Ingham, M. Stone, and J. Fisher, “Wear and Deformation of Ceramic-on-Polyethylene Total Hip Replacements With Joint Laxity and Swing Phase Microseparation,” Proc. Inst. Mech. Eng. H., 217 [2] 147–53 (2003).

58 Y. Takahashi, N. Sugano, W. Zhu, T. Nishii, T. Sakai, M. Takao, and G. Pezzotti, “Wear degradation of long-term in vivo exposed alumina-on-alumina hip joints: linking nanometer-scale phenomena to macroscopic joint design,” J. Mater. Sci. Mater. Med., 23 [2] 591–603 (2012).

59 J. Garino, M.N. Rahaman, and B.S. Bal, “The Reliability of Modern Alumina Bearings in Total Hip Arthroplasty,” Semin. Arthroplasty, 17 [3-4] 113–119 (2006).

60 J. Chevalier, S. Grandjean, M. Kuntz, and G. Pezzotti, “On the Kinetics and Impact of Tetragonal to Monoclinic Transformation in an Alumina/Zirconia Composite for Arthroplasty Applications,” Biomaterials, 30 [29] 5279–82 (2009).

61 “Recall of Zirconia Ceramic Femoral Heads for Hip Implants,” Bull. Am. Ceram. Soc., 80 [12] 14 (2001).

62 P. Merkert, “Next Generation Ceramic Bearings;” pp. 123–125 in Bioceram. Jt. Arthroplast. Steinkopff, 2003.

63 M. Kuntz, N. Shneider, and R. Heros, “Controlled Zirconia Phase Transformation in BIOLOX®delta - A Feature of Safety;” pp. 79–84 in Bioceram. Altern. Bear. Jt. Arthroplast. Steinkopff, New York, 2005.

64 B.J. McEntire, Y. Enomoto, W. Zhu, M. Boffelli, E. Marin, and G. Pezzotti, “Surface Toughness of Silicon Nitride Bioceramics: II, Comparison with Commercial Oxide Materials,” J. Mech. Behav. Biomed. Mater., 54 346–359 (2016).

65 G. Pezzotti, K. Yamada, S. Sakakura, and R.P. Pitto, “Raman Spectroscopic Analysis of Advanced Ceramic Composite for Hip Prosthesis,” J. Am. Ceram. Soc., 91 [4] 1199–1206 (2008).

66 G. Pezzotti, L. Puppulin, E. Casagrande, N. Sugano, B.J. McEntire, W. Zhu, and B.S. Bal, “On the Molecular Interaction Between Ceramic Femoral Heads and Polyethylene Liners in Artificial Hip Joints: I. Phenomenology,” TBD, [In Press] 1–8 (2016).

67 G. Pezzotti, B.S. Bal, E. Casagrande, N. Sugano, B.J. McEntire, W. Zhu, and L. Puppulin, “On the Molecular Interaction Between Ceramic Femoral Heads and Polyethylene Liners in Artificial Hip Joints: II. Molecular Scale Phenomena,” TBD, [In Press] 1–10 (2016).

68 B.J. McEntire, B.S. Bal, M.N. Rahaman, J. Chevalier, and G. Pezzotti, “Ceramics and Ceramic Coatings in Orthopaedics,” J. Eur. Ceram. Soc., 35 [16] 4327–4369 (2015).

69 T.J. Webster, G.A. Skidmore, and R. Lakshminarayanan, “Increased Bone Attachment to Silicon Nitride (Si3N4) Materials Used in Interbody Fusion Cages (IBF) Compared to Polyetheretherketone (PEEK) and Titanium (Ti) Materials - An In vivo Study;” pp. 1–5 in Proc. 2012 Annu. Meet. Orthopeaedic Soc. 2012.

70 M.P. Arts, J.F.C. Wolfs, and T.P. Corbin, “The CASCADE Trial: Effectiveness of Ceramic Versus PEEK Cages for Anterior Cervical Discectomy with Interbody Fusion; Protocol of a Blinded Randomized Controlled Trial,” BMC Musculoskelet. Disord., 14 [1] 244 (2013).

71 R.M. Taylor, J.P. Bernero, A.A. Patel, D.S. Brodke, and A.C. Khandkar, “Silicon Nitride - A New Material for Spinal Implants,” J. Bone Jt. Surg., 92-Br [Supp I] 133 (2010).

72 G. Pezzotti, R.M. Bock, B.J. McEntire, E. Jones, M. Boffelli, W. Zhu, G. Baggio, F. Boschetto, et al., “Silicon Nitride Bioceramics Induce Chemically Driven Lysis in Porphyromonas Gingivalis,” Langmuir, (2016).

73 Z Krstic, V Krstic, “Silicon nitride: the engineering material of the future” J Mater Sci 47:535–552 (2012).

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Advances in Biomaterials THE STORY OF SILICON NITRIDEcontent.stockpr.com/amedica/db/265/946/pdf/Executive+Summary+12.13... · Advances in Biomaterials . THE STORY OF SILICON NITRIDE