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Antimicrobial Coatings: The Research and Regulatory Perspective

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Coatings have long been considered an avenue for infection prevention in orthopedic procedures. These coatings, some of which utilize silver, have largely not been commercialized because regulators seek greater evidence of their safety, creating a long, expensive road for device companies. Announcements in the last half of 2018 and early 2019 indicate that companies continue to push to get them on the market and that productive conversations are taking place with regulators. This session began with a history of antimicrobial coatings followed by a look at recent research and technology.

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Antimicrobial Coatings: The Research and Regulatory Perspective

  1. 1. Webster’s Nanomedicine Lab Orthopedic Antimicrobial Materials: Fundamentals and Emerging Technologies Thomas J. Webster, Ph.D. Art Zafiropoulo Chair, Department Chair, Chemical Engineering Northeastern University, Boston, MA 02115 USA Past-President, U.S. Society For Biomaterials Fellow, AANM, AIMBE, BMES, FSBE, IJN, NAI, and RSM Editor, International Journal of Nanomedicine Associate Editor, Nanomedicine: NBM
  2. 2. The need: A brief overview of the numbers 20%-50% Bacterial infections Morbidity and Mortality 100,000 USD Growing market *2017 46 million USD 2025 67 million USD *Orthopedic Implants Market by Product Type (Reconstructive Joint Replacements, Spinal Implants, Dental Implants, Trauma, Orthobiologics, and Others), Biomaterial (Metallic, Ceramic, Polymeric, and Others), and Type (Knee, Hip, Wrist & Shoulder, Dental, Spine, Ankle, and Others): Global Opportunity Analysis and Industry Forecast, 2018 - 2025 2 But should anyone even believe these numbers, whether high or low ?
  3. 3. The bigger problem: Antibiotic resistant bacteria Staphylococcus aureus Staphylococcus epidermis Escherichia coli Pseudomonas aeruginosa 15% 66% Antimicrobial resistance (AMR) MRSA 3 Li, B.; Webster, T. J. Bacteria Antibiotic Resistance: New Challenges and Opportunities for Implant-Associated Orthopedic Infections. J. Orthop. Res. 2018, 36 (1), 22–32. https://doi.org/10.1002/jor.23656. *Methicillin resistant S. aureus
  4. 4. The Emergence of Antibiotic Resistant Bacteria https://www.cdc.gov/drugresistance/; https://amr-review.org/Publications.html Methicillin-resistant Staphylococcus aureus (MRSA) Colistin-resistant Escherichia coil (E.coil) 4 Bacterial antibiotic resistance causes • More than 2 million cases of illness and 23 thousand deaths annually (in the U.S. only) • In 2050, about 10 million deaths and will cost 100 trillion USD annually The bigger problem: Antibiotic resistant bacteria
  5. 5. The problems with infection…we created… Clatworthy AE, Pierson E, Hung DT. Nat. Chem. Bio. 2007;3:541-548 >2 million resistant infections/yr >23,000 deaths/yr $20 billion in excess direct healthcare costs Undesirable side-effects Longer treatment durations Immediate public health threat requiring urgent and aggressive action Antibiotic Resistance Threats in the United States, 2013. Center for Disease Control Number of Antibacterial New Drug Application Approvals per Year Decreased Pipeline of Solutions !!!
  6. 6. The race for the surface and… The race for a solution 6 Planktonic bacteria Biofilm Understanding bacteria 1 2 3 4 Arciola, C. R.; Campoccia, D.; Montanaro, L. Implant Infections: Adhesion, Biofilm Formation and Immune Evasion. Nat. Rev. Microbiol. 2018, 16 (7), 397–409. https://doi.org/10.1038/s41579-018- 0019-y.
  7. 7. The key is the surface Surface topography, grain structure, chemistry, and substrate stiffness all modulate cellular/bacteria functions.1-6 7 Cytoskeleton Integrin α β Ca2+ Fibronectin RGD Cell Substrate Cytoskeleton Integrin α β Ca2+ Fibronectin RGD Cell Substrate 1. Webster, T. J. et al., Biomaterials 21, 1803–1810 (2000). 2. Nikkhah, M. et al., Biomaterials 33, 5230–5246 (2012). 3. Bagherifard, S. et al., ACS Appl. Mater Interfaces 6, 7963–7985 (2014). 4. Guvendiren, M., Burdick, J. A., Nat. Commun. 3, 792 (2012). 5. Dolatshahi- Pirouz, A. et al., ACS Nano 4, 2874–2882 (2010). 6. Dolatshahi-Pirouz, A. et al., J. Funct. Biomater. 2 88–106 (2011).
  8. 8. So, the solution is the surface Some current approaches … 8 Coating film Physical/chemical modification Now, some examples… • Biocompatibility • Mechanical stability • Biofilm eradication • Stable drug-release • Regulatory approval The challenges… Materials with antimicrobial properties Ag, Cu, Ti, Zn…
  9. 9. Preventing bacteria adhesion 9 • Coatings: • Anti-bacterial adherence • Biocompatible Caro, A.; Humblot, V.; Méthivier, C.; Minier, M.; Salmain, M.; Pradier, C.-M. Grafting of Lysozyme and/or Poly(Ethylene Glycol) to Prevent Biofilm Growth on Stainless Steel Surfaces. J. Phys. Chem. B 2009, 113 (7), 2101–2109. https://doi.org/10.1021/jp805284s. Prevent the growth of tissue Polymer coating
  10. 10. • Antimicrobial peptides (AMPs) • Short chain • Amphoteric/cationic • Promote growth tissue 10 Preventing bacteria adhesion Ageitos, J. M.; Sánchez-Pérez, A.; Calo-Mata, P.; Villa, T. G. Antimicrobial Peptides (AMPs): Ancient Compounds That Represent Novel Weapons in the Fight against Bacteria. Biochem. Pharmacol. 2017, 133, 117–138. https://doi.org/10.1016/J.BCP.2016.09.018. Not susceptible to resistance AMPs
  11. 11. Self-assembling antibacterial cationic amphiphilic peptide (ACA-PA) 11 Nanoparticles self-assemble Dissolve peptide in water Simple preparation method Antimicrobial peptides
  12. 12. 12 MRSA MDR E.coli Control 80 µM ACA-nanorods treated Scale bar= 200 nm Antimicrobial peptides Commercialized by Audax, Inc.
  13. 13. Preventing bacteria adhesion 13 • Surface modification: changing morphology • Nanostructured surfaces Peng, Z.; Ni, J.; Zheng, K.; Shen, Y.; Wang, X.; He, G.; Jin, S.; Tang, T. Dual Effects and Mechanism of TiO2 Nanotube Arrays in Reducing Bacterial Colonization and Enhancing C3H10T1/2 Cell Adhesion. Int. J. Nanomedicine 2013, 8, 3093–3105. https://doi.org/10.2147/IJN.S48084. Titaniumsurface Titanium nanotubes Bacterial growth Cell growth TiO2 nanotubes
  14. 14. Nanotube surfaced abutment study, Rhode Island Veteran’s Administration Hospital Nanotubes with added bactericidal agent in guinea pig model. Textured surfaces can improve vascularized tissue attachment and provide a mechanism for storing and releasing bactericidal agents. Preventing bacteria adhesion and creating bactericidal surfaces As commercialized by Nanovis, LLC
  15. 15. Why ??? Nanostructures in Nature Pogodin et al. Biophysical model of bacterial cell interactions with nanopatterned cicada wing surfaces. Biophys. J. 2013, 104, 835-840. The nanopillar structures of the wing surface are spaced 170nm apart from center to center. Each pillar is ~200nm tall, with a conical shape and a spherical cap 60nm in diameter. 500nm It has been found that the nanopillars on cicada wings are inherently antibacterial, irrespective of surface chemistry. • Results show that the cicada wing surface appears to be bactericidal to Pseudomonas aeruginosa.
  16. 16. Biophysical model of bacterial cell interactions with nanopillars Mechanism: As the bacteria try to attach onto the nanopillar structures, the cell membrane stretches in the regions suspended between the pillars. If the degree of stretching is sufficient, this may lead to no attachment or cell rupture. Pogodin at al. Biophysical model of bacterial cell interactions with nanopatterned cicada wing surfaces. Biophysical Journal, Volume 104, pp. 835-840, 2013. Possible Reason: Biophysical model
  17. 17. Contact killing bacteria • Immobilization of bactericidal agents • Functional groups surface • Controlled drug delivery 17 Jose, B.; Antoci, V.; Zeiger, A. R.; Wickstrom, E.; Hickok, N. J. Vancomycin Covalently Bonded to Titanium Beads Kills Staphylococcus Aureus. Chem. Biol. 2005, 12 (9), 1041–1048. https://doi.org/10.1016/J.CHEMBIOL.2005.06.013. Drug immobilization AMR AMPs
  18. 18. Contact killing bacteria • Injected metal ions • Metallic nanoparticles inside surfaces • Different combinations… • Ti-AgNPs • Ti-CuNPs 18 Plasma immersion implantation (PII) No planktonic bacteria Wang, G.; Jin, W.; Qasim, A. M.; Gao, A.; Peng, X.; Li, W.; Feng, H.; Chu, P. K. Antibacterial Effects of Titanium Embedded with Silver Nanoparticles Based on Electron-Transfer-Induced Reactive Oxygen Species. Biomaterials 2017, 124, 25–34. https://doi.org/10.1016/J.BIOMATERIALS.2017.01.028.
  19. 19. Contact killing bacteria • Assembly of different materials • Combination of properties • Materials normally used • Polymers • Peptides • Nanoparticles 19 Layer-by-layer films Enhanced biocompatibility and tissue regeneration Shi, Q.; Qian, Z.; Liu, D.; Liu, H. Surface Modification of Dental Titanium Implant by Layer-by- Layer Electrostatic Self-Assembly. Front. Physiol. 2017, 8, 574. https://doi.org/10.3389/fphys.2017.00574.
  20. 20. Inhibiting biofilm formation • Most challenging step • Enzyme inhibition • Target bacterial external substances • Enzyme loaded inside polymeric NPs • Effective drug delivery 20 Bacterial external substances Loaded nanoparticles Tan, Y.; Ma, S.; Liu, C.; Yu, W.; Han, F. Enhancing the Stability and Antibiofilm Activity of DspB by Immobilization on Carboxymethyl Chitosan Nanoparticles. Microbiol. Res. 2015, 178, 35–41. https://doi.org/10.1016/J.MICRES.2015.06.001
  21. 21. Inhibiting biofilm formation • Quorum sensing inhibition (QS) • Target bacterial communication system • Inhibitors interfere the signaling process • Small molecules: AgNPs… 21 Quorum sensing Truchadoa, et al., 2015 Ravindran, D.; Ramanathan, S.; Arunachalam, K.; Jeyaraj, G. P.; Shunmugiah, K. P.; Arumugam, V. R. Phytosynthesized Silver Nanoparticles as Antiquorum Sensing and Antibiofilm Agent against the Nosocomial Pathogen Serratia Marcescens : An in Vitro Study. J. Appl. Microbiol. 2018, 124 (6), 1425–1440. https://doi.org/10.1111/jam.13728.
  22. 22. 22 The ultimate goal Sensing, determining and providing personalized medicine “Smart” implants An example…
  23. 23. Basic Components of a Closed-Loop Orthopedic Sensor and Drug Administration Real-time Detection of Cells Surrounding an Orthopedic Implant Gold Connectors Platinum MWCNT-Ti Ag/AgCl “Hand wand” to gather information (collaboration with OrthoTag) Commercialized by NanoPolymer Solutions
  24. 24. ConclusionsOrthopedic implant surfaces can be modified via: • Coatings, • Nanotextured surfaces, • Nanomedicine (nanoparticles), and/or • Self assembled nanomaterials To reduce the growing problem with antibiotic resistant orthopedic implant infections. 24 Treated MRSA Treated MDR Summary But the future is in implantable sensors…

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