1. The Bactiguard Technology
Nina Nilsson, Director of Marketing
4/23/2019
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2. Swedish based R&D Introduction
Markaryd and new site next to Karolinska Hospital, Alfred Nobels road!
Product and coating development, Sweden
Microbiology & cell lab, Sweden
4/23/2019
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3. Production R&D coating, BIP CVC Production
Production, Bactiguard coating
Production
Production, upscale
4/23/2019
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4. FOR INTERNAL USE ONLY - DO NOT DISTRIBUTE
AGENDA
Unique sustainable coating
Prevents microbial adhesion and biofilm
Non-toxic and tissue friendly
Blood compatible – non-thrombogenic
Does not trigger immune reactions
4/23/2019
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5. FOR INTERNAL USE ONLY - DO NOT DISTRIBUTE
Unique coating
Three (3) noble metals in metallic forms (Ag, Pd, Au)
Very thin – small amounts of metals
Palladium and gold
Silver
Underlying material
ToF-SIMS measurement of Bactiguard® coated latex.
4/23/2019
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6. Sustainable, non-releasing
For BIP Foleys, % of the coating remains after 90 days use (lab)
TD, Report for simulated 3 months of use for BIP Foley Latex and Silicon
For BIP CVC, % of the coating remains after 14 days in blood in patient
4/23/2019
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7. FOR INTERNAL USE ONLY - DO NOT DISTRIBUTE
Material we can coat Ti
SILICON ELASTOMERS (PDMS)
POLYVINYL CHLORIDE (PVC)
NYLON
MAGNESIUM
LATEX
SILICA
POLYSTYROLE (PS)
POLYPROPYLENE (PP)
POLYARYLETHERKETONE (PEEK)
LATEX
POLYIMIDE (PI)
POLYURETHANE (PU)
POLYAMIDE (NYLON)
COPPER
ETHYLENEVINYLACETAT (EVA)
GLASS
NONWOVEN
NONWOVEN MATERIALS
STAINLESS STEELS
ZIRCONIUM
CERAMICS
TELFLON (PTFE)
SILICONE
POLYMETHYLMETACRYLATE (PMMA)
TEXTILES
PVC
ZEOLITES
TITANIUM
POLYESTER
ALUMINIUM
4/23/2019
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CERAMIC

8. FOR INTERNAL USE ONLY - DO NOT DISTRIBUTE
Potential devices
CVC CATHETERS
DENTAL IMPLANTS
BLOOD BAGS
STENTS
CONTACT LENSES
PACEMAKER
IMPLANTS
ARTIFICIAL HEART VALVES
SURGICAL INSTRUMENTS
SUTURES
HEMODIALYSIS EQUIPMENT
RUPTURE NETS
PERIPHERAL STENTS
DRUG DELIVERY DEVICES
EKG ELECTRODES
SUTURES
WOUND DRESSING
INTRAOCULAR LENSENS
TISSUE REPLACING IMPLANTS
GRAFTS
ENDOTRACHEAL TUBINGS
NEEDLES
4/23/2019
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9. 1- Unique sustainable coating
3 noble metals, metallic
Very thin – small amounts
Sustainable (up to 3 months), non-releasing
Can be applied to any surface
4/23/2019
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10. FOR INTERNAL USE ONLY - DO NOT DISTRIBUTE
AGENDA
Unique sustainable coating
Prevents microbial adhesion and biofilm
Non-toxic and tissue friendly
Blood compatible – non-thrombogenic
Does not trigger immune reactions
4/23/2019
FOR INTERNAL USE ONLY - DO NOT DISTRIBUTE

11. Biofilm formation – a starting point for infections
A few seconds
A few hours
A few days
When enough bacteria have developed, they form a biofilm. If they begin to disperse, there
is an incresed risk of infection.
Bacteria begin to
adhere to the surface.
Bacteria begin to multiply.
Catheter surfaces (without coating) easily attract bacteria, which develop into a biofilm. Catheter associated urinary tract infections occur when there is an inflammatory response to bacteria in the urethra or bladder.
In short, the process is that bacteria in the surroundings attach to the surface of the catheter, after a few hours they begin to multiply and after approximately 2 days they have mobilised so that they can start building biofilm. This is often the start for the infection, that could also begin to spread and cause the more severe condition sepsis.
Uncoated surface
4/23/2019
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12. The Bactiguard® coating
Gold Au
Silver Ag
A galvanic effect is
created due to the noble metals in the fluids (urine/blood)
Palladium Pd
Bacteria
The Bactiguard Infection Protection (BIP) technology is based on applying an extremely thin noble metal coating, consisting of gold, silver and palladium, to medical devices. The Bactiguard® coating is firmly bound to the
surface of the device and reduces the adhesion and growth of microbes.
The three noble metals in the Bactiguard coating – gold, silver and palladium, cause a galvanic effect which leads to a micro current that prevent the bacteria to adhere to the surface.
The solution is unique. As opposed to coating technologies, which depend on the release of toxic substances e.g. silver ions or antibiotics, the Bactiguard coating is non-toxic and non-pharmacologic. To date, more than130 million Bactiguard® coated urinary catheters have been sold for patient use, with no reported adverse events related to the coating.
The current prevents bacteria from adhering to the surface
This creates a
micro current
4/23/2019
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13. The galvanic (battery) effect
The electro potential difference between the noble metals in the coating that gives rise to galvanic action on the surface when in contact with an electrolyte.
When metals with a potential difference are connected via a salt brighe, like urine, a electric energy is generated. This is what happends between the metals in the Bactiguard coating. This is something our inventor, Billy always thought, and now we have been able to prove it.
4/23/2019
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14. FOR INTERNAL USE ONLY - DO NOT DISTRIBUTE
The galvanic effect
Atomic Force Microscope- Voltage over a coated sample generates pico currents
The instrument is not made to have a salt bridge. so instead 1 volt is put over the sample. In the uncoated sample, the voltage. ´Which shows that a current is generated from the coated surface, which gives the battery effect. This is believed to be unfavourable for the bacterial to adhere to the surface.
4/23/2019
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15. The Bactiguard surface
250 nm
500 nm
Electro potential difference, Electric Force Microscopy
Bactiguard® coated Latex, photo from TOF-SIMS
Palladium
Silver
2,00 V/Div
Time-Of-Flight Secondary Ion Mass Spectroscopy on latex
4/23/2019
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16. Bards description on Mechanism of action
4/23/2019
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17. The Bactiguard® coating in comparison to releasing technologies
For exampel: Traditional silver release technology
Surface coating
Silver Ag
Many healthcare professionals are familiar with tradtional coating technologies that depend on release of substances, for example large amounts of silver ions, antibiotics or chlorhexidine. This is a very different mechanism of action than the Bactiguard technology. As an example a ”silver catheter” can have 5-10 times more silver than a Bactiguard coated catheter, even if also the latter contains some silver. The mechanism of action with the silver technologies, as opposed to BIP, is that large amounts of silver ions are being released from the surface to actively kill bacteria. The downside is that the effect is not sustaining as the coating is being released, and it can be very aggresive to surrounding tissue – even causing inflammatory responses itself.
The FDA and other authorities have issued several warnings related to these type of coatings.
Silver ions are released from
the surface, killing bacteria.
5 to 10 times thicker layer than a surface with Bactiguard coating. Becomes thinner over time.
4/23/2019
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18. Bactiguard coating prevents bacterial adhesion and biofilm formation
Foley without coating
An Ahearn test is an in vitro test to evaluate the adhesion of microorganisms to device surfaces. In this test we allow bacteria to grow on an uncoated Foley and a Bactiguard coated Foley, then shake off the bacteria on an Agar plate to quantify the bacteria.
In the images to the left we see the same thing through a scanning electron microscope (SEM).
Foley with Bactiguard coating
4/23/2019
*Center for Applied and Environmental Biology, Georgia State University, Atlanta. Manal Gabriel et al., CURRENT MICROBIOLOGY Vol. 30 (1995), pp Donald G. Ahearn et.al., CURRENT MICROBIOLOGY Vol. 41 (2000), pp. 120–125
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19. FOR INTERNAL USE ONLY - DO NOT DISTRIBUTE
BIP Foley Catheter
In vitro data 5 relevant microbial strains reduction of bacterial adhesion BIP Foley (latex) compared to uncoated Foley in latex.
4/23/2019
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20. BIP Foley Catheter Silicone
In vitro data 5 relevant microbial strains reduction of bacterial adhesion BIP Foley silicone compared to uncoated Foley silicone.
4/23/2019
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21. FOR INTERNAL USE ONLY - DO NOT DISTRIBUTE
BIP CVC
In vitro data 3 relevant microbial strains reduction of bacterial adhesion BIP CVC compared to uncoated CVC
4/23/2019
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22. FOR INTERNAL USE ONLY - DO NOT DISTRIBUTE
BIP ETT
Representative average reduction in microbial adhesion to BIP ETT
BIP ETT
S. aureus
P. aeruginosa
S. sanginosa
N. elongate
E. coli
Bacterial strain
% reduction in bacterial adhesion
>90% reduction in bacterial growth in relevant strains1
The table shows In vitro data for 5 relevant bacterial strains and their reduction compared to uncoated ETT.
4/23/2019
1. Data on file
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23. Reduction of biofilm in clinics
“Eurobiofilms 2009” conference, Rome (Sept 02-05, 2009).
Bactiguard Infection Protection by biofilm former bacteria in
urological long-term patients.
Mazzoli S.*, Meacci F.*, Cai T.§, Bartoletti R.§
*STDs Center, Santa Maria Annunziata Hospital, ASL 10 Florence, Italy
§ Urology Unit, Santa Maria Annunziata Hospital, University of Florence, Florence, Italy
BIP Foley
Standard Foley
Positive (biofilm)
6 (33%)
15 (79%)
Negative (no biofilm)
12 (67%)
4 (21%)
Total 18 19
37 long term (>30 days) catheterized urological-surgical patients
58% reduction of biofilm occurrence on BIP Foleys
4/23/2019
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24. FOR INTERNAL USE ONLY - DO NOT DISTRIBUTE
AGENDA
Unique sustainable coating
Prevents microbial adhesion and biofilm
Non-toxic and tissue friendly
Blood compatible – non-thrombogenic
Does not trigger immune reactions
4/23/2019
FOR INTERNAL USE ONLY - DO NOT DISTRIBUTE

25. Non-toxic levels of coating metals
Silver, Ag, exposure:
In normal case: at least 1000 x lower than Toxicological safety Limit for chronic use (Safety margin )
In Worst Case: 100 x lower (Safety margin 102)
Gold, Au, exposure:
In normal case: x lower than Toxicological safety Limit for chronic use (Safety margin )
In Worst Case: 100 x lower (Safety margin 102)
Palladium, Pd, exposure:
In normal case: 1000 x lower than Toxicological safety Limit for chronic use
(Safety margin 103)
In Worst Case: 2-10 x lower (Safety margin 101)
The use of the BIP Foley & BIP CVC is safe from a perspective of silver, palladium and gold exposure, even in the case of rare chronic use.
* reference-dose of chronic, oral administration (RfD) United States Environmental Protection Agency: mg/kg/day)
** Permitted Daily Exposure (PDE) derived from NOAEL-values, by the CHMP (Committee for Medicinal Products for Human Use) at EMA, PDE for chronic use, the parenteral administration-route for palladium: 10 μg/day
*** The calculated safety limit for gold exposure, based on the lowest recommended therapeutic dose for Auranofin (a gold salt) and adjusted with an uncertainty factor of 10 for the administration route: 87 µg /day 25
4/23/2019
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26. Non-toxic properties tested in cells and animals
Further animal and cell line tests (accredited GLP lab)
No acute toxicity in mice tests Non-toxic in 4 weeks sub-chronic use in rats Non-genotoxic in cell-culture assay – Ames test (no mutations) Not cytotoxic to cells (mouse lymphoma cells)
4/23/2019
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27. Results of Implantation Levels of Urethral Damage
Tissue compatibility The Bactiguard coating lowers the natural cytotoxicity of latex
The effect of different materials on the rat urethral mucosa. Strips of catheters of different materials and coating were inserted into the urethra of 100 rats. After 72 h the damage was assessed using a 4-graded scale. The Bacti-Guard®/Hydrogel was as biocompatible as the control. Data on file.
1 Undamaged
2 Partial Damage
3 Moderate Damage
4 Severe Damage
Rubber
Latex
Latex/Hydrogel
Latex/Bacti-Guard
Latex/Bacti-Guard/
Hydrogel
Control – Cystotomy only
0.5 1
1.5 2
2.5 3
3.5 4
Results of Implantation
Levels of Urethral Damage
I this study by Liedberg et al, different material cytotoxic properties have been assesed on urethral mucosa (rat). Results show that Bactiguard and hydrogel coated latex (like BIP Foley Catheter) is significantly less aggressive to the tissue compared to rubber, latex, hydrogel coated latex etc. on a scale 1-4 on how much damage could be observed in a microsope.
Bactiguard coating seems to recude the toxic properties of latex, and is so more tissue friendly.
SUMMARY:
The tissue compatibility can be greatly enhanced by using the BIP Foley catheter
4/23/2019
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28. FOR INTERNAL USE ONLY - DO NOT DISTRIBUTE
AGENDA
Unique sustainable coating
Prevents microbial adhesion and biofilm
Non-toxic and tissue friendly
Blood compatible – non-thrombogenic
Does not trigger immune reactions
4/23/2019
FOR INTERNAL USE ONLY - DO NOT DISTRIBUTE

29. Introduction to coagulation
(+) Coagulation preservs body from the bleeding (hemostasis)
(-) Uncontrolled life threatening clots can be formed (thrombosis)
Coagulation system overlaps with the immune system – blood clots can trap in bacterias, some coagulation proteins are anti-microbial or may cause inflammation
4/23/2019
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30. Coagulation Thrombosis Thrombin-Antithrombin Blood (platelets)
Fibrinogen
Thrombin
Activation
Fibrin
Blood clot
Thrombosis
4/23/2019
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31. FOR INTERNAL USE ONLY - DO NOT DISTRIBUTE
Blood compatibility
Biocompatibility
Whole blood analysis, platelets
Plasma analysis, coagulation factors, inflammation markers
Centrifugation
Coagulation factors significant lowered
Less platelets stuck to the device
Less thrombosis!
4/23/2019
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32. Hemolysis and blood compatibilty
ARROW g+ard
Chlorohexidine
Silver sulphadiazine
BIP CVC
Bactiguard coated
Uncoated
BIP CVC does not cause haemolysis as opposed to Arrow G+ard blue
4/23/2019
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Bactiguard internal data; (Exposure time 5, 10, 15, 30 and 60 minutes) 32

33. Hemolysis and blood compatibility
BIP CVC
ARROW
The blood compatibility of BIP CVC is superior to Arrow G+ard blue
4/23/2019
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34. FOR INTERNAL USE ONLY - DO NOT DISTRIBUTE
Platelets and Fibrinogen do not stick to Bactiguard coating; coagulation factors are not activated (TAT low) *
“one of the individual noble metals, Ag, Au, and Pd, can alone explain the low coagulation and immune complement response on the Bactiguard commercial surface”
4/23/2019
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35. Visible blood fibrin clots
Uncoated CVC
BIP CVC
4/23/2019
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36. Biocompatibility – Blood compatibility – Clinical evidence
No patients
236
Patient type
Haematologic and oncologic diseases
Median time for catheterization : 13,3/12,7 days
Design
Prospective, randomized
Site
University of Heidelberg, Germany
Primary outcome
Catheter related infection
Other
Local catheter infection
Catheter related bacteremia
Additionally
The risk for trombosis was evaluated by Harter et al who found no increased risk in the Bactiguard group
4/23/2019
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37. FOR INTERNAL USE ONLY - DO NOT DISTRIBUTE
AGENDA
Unique sustainable coating
Prevents microbial adhesion and biofilm
Non-toxic and tissue friendly
Blood compatible – non-thrombogenic
Does not trigger immune reactions
4/23/2019
FOR INTERNAL USE ONLY - DO NOT DISTRIBUTE

38. Introduction to the immune system
(+) Innate and adaptive immune system defends against infection
(-) Innate immune system reacts at any foreign matter, including implants and devices
Low stimulation can be positive – prepares the body to fight infections
Extensive stimulation can give inflammation, implant rejection, …
4/23/2019
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39. Bactiguard coating does not trigger immune reactions
Immune response
C3a - marker for immune reaction
C3a similar for Bactiguard coated Titanium as for pure Titanium
C3a is a molecule that trigger our immune response. C3a can be measured in the blood after exposure of a device, for example in the Chandler loop model. These results are from a similar model.
Hulander M et al, Blood interactions with noble metals: coagulation and immune complement activation. ACS Appl Mater Interfaces May;1(5):
4/23/2019
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40. Osseointegration - Immune response
12 weeks implantation of titanium screws in rabbit
Bactiguard coated
Uncoated
Svensson S, et al,. Osseointegration of titanium with an antimicrobial nanostructured noble metal coating. Nanomedicine Oct;9(7):
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41. FOR INTERNAL USE ONLY - DO NOT DISTRIBUTE
SUMMARY
Unique sustainable coating
Prevents microbial adhesion and biofilm
Non-toxic and tissue friendly
Blood compatible – non-thrombogenic
Does not trigger immune reactions
4/23/2019
FOR INTERNAL USE ONLY - DO NOT DISTRIBUTE