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.

2. 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

3. 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 ?

4. 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

5. 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

6. 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 !!!

7. 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.

8. 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).

9. 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…

10. 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

11. • 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

12. Self-assembling antibacterial cationic
amphiphilic peptide (ACA-PA)
11
Nanoparticles
self-assemble
Dissolve peptide
in water
Simple preparation method
Antimicrobial peptides

13. 12
MRSA
MDR
E.coli
Control 80 µM ACA-nanorods treated
Scale bar= 200 nm
Antimicrobial peptides
Commercialized by Audax, Inc.

14. 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

15. 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

16. 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.

17. 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

18. 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

19. 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.

20. 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.

21. 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

22. 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.

23. 22
The ultimate goal
Sensing, determining and providing personalized medicine
“Smart” implants
An example…

24. 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

25. 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…