Engineering Bacteriostatic Behavior Into Implantable Medical Devices

Transcription

1 Engineering Bacteriostatic Behavior Into Implantable Medical Devices Bryan J. McEntire, Ph.D., MBA Ceramics Expo 2017 Cleveland, OH, USA April 27, 2017 A M E D I C A 1

2 Part I: The need for infection resistant biomaterials. A M E D I C A 2

3 A Brief History of Prosthetic Joint Infections 3.25 billion years ago Biofilms first appear in the fossil record First antibiotic compound (Penicillin) discovered. 1960s Joint replacements initiated with PJI rates of 5% to 10% s - Improved surgical theaters and physician practice reduce PJI rates to between 3% and 5% s-1980s Widespread use of prophylactic antibiotics reduces PJI rates to <1% to 3% s-2010s Despite advancements in biomaterials, the incidence MRSA PJI has not only plateaued, it is now increasing

4 Projected Incidence of USA PJI Cases Infection Rates: : 0.7 to 2.25% : +2.25%? Prosthetic joint infections are expected to cost US hospitals $1.68 billion by 2020, with treatment costs of 2.8x to 4.8x revision and primary surgeries, respectively

5 Innovations Enabling Routine Invasive Surgery Development of modern anesthesia. 6 Use of prophylactic and perioperative antibiotics. 7 What would happen if we lost one of these key practices? 5

6 Estimated Mortality Rates due to Infection United States 2016 Estimate 8-9 Worldwide 50, , Estimate Million 6

7 Antibiotic Resistance Timeline Antibiotic Discovery Antibiotic Resistance Penicillin (2 Years) Colistin 1959 Vancomycin 1972 Imipenem (16 Years) 1998 (13 Years) Daptomycin 2003 Adapted from: CDC Brochure, Ref. [10] (1 Year) 2016 (57 Year) 7

8 Is the Golden Age of Antibiotics Over? This is huge. We are one step away from CRE strains that cannot be treated with antibiotics. Dr. Lance Prince, George Washington University Researcher. 11 We risk being in a post-antibiotic world. The medicine cabinet is empty for some patients. Dr. Thomas R. Frieden, Director of the Centers for Disease Control and Prevention. 11 8

9 The Need for Bacterial Resistant Biomaterials An ageing population seeks to maintain or improve their quality of life. There is growing antibiotic resistance among all common nosocomial bacterial strains. There is a large economic and social burden associated with treating infections. Novel strategies are necessary for the post-antibiotic era. 9

10 Part II: Engineering Bacteriostasis into Biomaterials A M E D I C A 10

11 Definition of Bacteriostasis The capability of a biomaterial to metabolically interfere with bacteria to prevent attachment, growth, or reproduction. This differs from bactericidal materials, which are designed to outright kill the microorganism. Staphylococcus biofilm 11

12 Biofilm The Life of a Microbe From: C. Bordi, et al., Reference [12]; Reproduced in part with permission. 12

13 Abiotic Material Strategies to Prevent Biofilm Micro/nano surface textures. Highly hydrophilic treatments or coatings. Highly hydrophobic treatments or coatings. Incorporation of elutable chemical disinfectants. Hydrophilic zwitterionic engineered surfaces or coatings. Surfaces that promote rapid tissue integration. Biofilm degrading agents or compounds that interfere with quorum sensing. Grafted cationic peptides, chitosan and its quaternized derivatives. Doped photoactivated surfaces. Adapted from : D. Campoccia et al., Ref. [13], and C. R. Arciola, et al., Ref. [14]. 13

14 Preventing Biofilms General Guidance Surface Topography Micro-rough surfaces facilitate bacterial adhesion. Nano-rough surfaces have the opposite effect. Surface Charging and Hydrophilicity Moderately hydrophobic surfaces promote adhesion. Large negatively charged surfaces inhibit attachment. Surface Chemistry Zwitterionic-like surfaces inhibit adherence. Elutable chemical moieties can act as local biocides. Effect of Proteins Surface charge and hydration affect adsorption. Proteins can facilitate or hinder bacterial attachment. Adapted rom: Y. F. Missirlis and M. Katsikogianni, Ref. [16-17]. 14

15 Part III: Bacteriostasis A Si 3 N 4 Case Study A M E D I C A 15

16 In vitro Bacteriostatic Behavior of Biomaterials Pseud. aeruginosa SN AF SN Polished Ti PEEK E. coli SN AF SN Polished Ti PEEK Adapted from D. J. Gorth, et al., Ref. [18]; used with permission. 16

17 In vitro Bacteriostatic Behavior of Biomaterials S. epi SN AF SN Polished Ti PEEK S. aureus SN AF SN Polished Ti PEEK Adapted from D. J. Gorth, et al., Ref. [18]; used with permission. 17

18 In vitro Bacteriostatic Behavior of Biomaterials Enterococcus SN AF SN Polished Ti PEEK Adapted from D. J. Gorth, et al., Ref. [18]; used with permission. 18

19 In vitro Bacteriostatic Behavior of Biomaterials Staph. E. coli epi. R. M. Bock, et. al., Bacteriostatic Behavior of Surface-Modulated Silicon Nitride in Comparison to Polyethereetherketone and Titanium, J. Biomed. Mater. Res. Part A. 1-35, (2016). 19

20 In vivo Bacteriostatic Behavior of Biomaterials Wistar Rat Calvarial Study Implant Infection PEEK Si 3 N 4 Ti Histology performed 3 months after 10 4 Staph. epi. septic implantation. Si 3 N 4 had significantly higher bone reformation in the defect area and at the implant interface with no presence of bacteria within the surgical site. Adapted from: T. J. Webster et al., Reference [19]; used with permission. 20

21 P. Gingivalis Undergoes Lysis when Exposed to Si 3 N 4 Fluorescence microscopy after staining with propidium iodide (PI) and 5-(and 6)- carboxyfluorescein diacetate (CFDA) solutions 2 μm G. Pezzotti, et al., Silicon Nitride Bioceramics Induce Chemically Driven Lysis in Porphyromonas Gingivalis, Langmuir, 32, , (2016). 21

22 Si OH Surface Chemistry and Morphology of Si 3 N 4 Si OH () Si O () Oxygen-rich Nitrogen-rich Balance of Surface Functional Groups + H () Si NH Si NH 2 Si NH () + H () Si 3 N 4 Polished AF Si 3 N 4 R a = 2nm R q = 5nm = 47 3 R a = 641nm R q = 830nm = after 30 min. From: R. M. Bock, et al., Ref. [20]. 22

23 Differences in Wetting Behavior 23

24 Zeta () Potentials of Biomaterials -Potentials at ph7.4 Oxidized Si 3 N 4-70mV N 2 -annealed Si 3 N 4-60mV As-fired Si 3 N 4-45mV Ti6Al4V -15mV 24

25 Si 3 N 4 s Elutable Surface Chemistry Surface chemistry consists of silicon diimide Si(NH) 2 groups which release ammonia (NH 3 ) and silicic acid (H 4 SiO 4 ) into biological fluids. 1,2 Bioavailable silicon (H 4 SiO 4 ) is essential for rapid bone reformation G. Pezzotti, "Bioceramics for Hip Joints: The Physical Chemistry Viewpoint." Materials, 7.6, , (2014). 2. R. C. Dante, et al., A Review and a Fundamental Theory of Silicon Nitride Tribochemistry, Wear, 288, (2012). 3. R. Jugdaohsingh, "Silicon and Bone Health." Journal of Nutrition, Health & Aging, 11.2, , (2007). 25

26 Chemical Lysis Mechanism Silanol Ammonia - Superoxide radical Superoxide Peroxynitrite G. Pezzotti, et al., Silicon Nitride Bioceramics Induce Chemically Driven Lysis in Porphyromonas Gingivalis, Langmuir, 32, , (2016). 26

27 Conclusions and Significance A higher incidence of PJI is forecast due to increasing demands for TJA procedures and antibiotic resistant bacterial strains. Development of bacteriostatic biomaterials are one of a number of strategies needed to combat antibiotic resistance. Si 3 N 4 shows promise as a bioactive and interactive prostheses in inhibiting biofilm formation. The bacteriostatic mechanisms of Si 3 N 4 may be multivariate. 27

28 References 1. L. Hall-Stoodley, et al., Bacterial Biofilms: From the Natural Environment to infectious Diseases, Nat Rev Micro, 2, , (2004). 2. L. Lidgren, Joint Prosthetic Infections: A Success Story, Acta Orthop., 72, , (2001). 3. S. Kurtz, et al., Infection Burden for Hip and Knee Arthroplasty in the United States, J. Arthroplasty,23, , (2008). 4. D. J. Jaekel, et al., Epidemiology of Total Hip and Knee Arthroplasty Infection, In Periprosthetic Joint Infection of the Hip and Knee; Springer: New York, 2014; pp C. J. Gutowski, et al., The Incidence and Socioeconomic Impact of Periprosthetic Joint Infection: United States Perspective, In Periprosthetic Joint Infections: Changing Paradigms; D. Kendoff, et al., Eds.; Springer International Publishing: Cham, 19 26, (2016). 6. R. Urman et al., History of Anesthesia for Ambulatory Surgery, Curr. Opin. Anaesthesiol. 25(6):641 7, (2012). 7. J. Clardy et al., The Natural History of Antibiotics, Curr. Biol. 19(11):437 41, (2009). 8. Review on Antimicrobial Resistance (London), and Grande-Bretagne. Antimicrobial resistance: Tackling a crisis for the health and wealth of nations. Review on Antimicrobial Resistance, J. Carlet et al., Ready for a World Without Antibiotics? The Pensières Antibiotic Resistance Call to Action, Antimicrob. Resist. Infect. Control 1(1):11, (2012). 10. T. Frieden, Antibiotic Resistance Threats in the United States, CDC Brochure, (April 23, 2013). 11. Infection Raises Specter of Superbugs Resistant to All Antibiotics, NYTimes.com, (Accessed May 27, 2016). 12. C. Bordi et al., Hacking into Bacterial Biofilms: A New Therapeutic Challenge, Ann. Intensive Care, 1, 1 8 (2011). 13. D. Campoccia, et al., A Review of the Biomaterials Technologies for Infection-Resistant Surfaces, Biomaterials, 34, , (2013). 14. C. R. Arciola, et al., Biofilm Formation in Staphylococcus Implant Infections. A Review of Molecular Mechanisms and Implications for Biofilm- Resistant Materials. Biomaterials, 33, , (2012). 15. E. P. Ivanova, et al., Natural Bactericidal Surfaces: Mechanical Rupture of Pseudomonas Aeruginosa Cells by Cicada Wings, Small, 8, , (2012). 16. Y. F. Missirlis and M. Katsikogianni, Theoretical and Experimental Approaches of Bacteria-Biomaterial Interactions, Materwiss. Werksttech., 38, , (2007). 17. M. Katsikogianni, Concise Review of Mechanisms of Bacterial Adhesion to Biomaterials and of Techniques Used in Estimating Bacteria-Material Interactions, Eur. Cells Mater., 8, (2004). 18. D. J. Gorth, et al., Decreased Bacteria Activity on Si 3 N 4 Surfaces Compared with PEEK or Titanium. Int. J. Nanomedicine, 7, , (2012). 19. T. J. Webster et al., Anti-Infective and Osteointegration Properties of Silicon Nitride, Poly(etheretherketone), and Titanium Implants, Acta Biomaterialia, 8, [12], , (2012). 20. R. M. Bock, et al., Surface Modulation of Silicon Nitride Ceramics for Orthopaedic Applications. Acta Biomater., 26, , (2015). 28

29 Thank you for your attention. 29