ISE 789 -- Using Bactericidal Metals for Infections

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ISE 789 -- Using Bactericidal Metals for
Infections
Richard A. Wysk And Thomas Fuller
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Overview

• Background
• Osteomyelitic infections within prosthetics
• Silver as an antibiotic agent
• Silver Design
• Testing Analysis
• Development Cost Analysis
• Conclusions

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Drug-resistant infections kill more Americans
than AIDS and breast cancer combined.
30 billion Cost of
hospital/health care associated infections. 1.7
million Patients get
health care associated infections. 100,000
Annual deaths from hospital
infections.
June 19, 2006
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Osteomyelitis

• Bone infection regardless of origin
• Characterized by destruction of bone followed by
  new bone formation
• Course
• Bacterial introduction
• Inflammatory response
• Small vessel thromboses
• Increased intraosseous pressure
• Resulting in less blood flow

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Medical/Dental/Veterinary Applications
March 24, 2006 (Chicago) -- The number of total
knee replacements performed in the U.S. will leap
by 673 -- reaching 3.48 million -- by the year
2030, according to a new study presented at the
73rd annual meeting of the American Academy of
Orthopaedic Surgery in Chicago. Hip replacements
will increase by 174 to 572,000 by 2030,
according to the new findings, which are based on
historical procedure rates from 1990 to 2003, and
on population projections from the U.S. Census
Bureau.
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Veterinary Applications
Implants that spawned infection
Fractured leg
Kentucky Derby winner Barbaro suffers a fractured
leg and develops a serious infection after
surgery with implanted plate and screws.
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Treatment of Osteomyelitis

• Difficult to treat (Bacteria)
• Express receptors / adhesions allowing adherence
  to bone or implants
• Antibiotic resistance
• Glycocalyx Slime layer

1999-2000 KUMC Pathology and the University of
Kansas,
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Treatment of Osteomyelitis

• Difficult to treat (Bone)
• Bone Microcirculatory structure sensitive to
  bacterial toxins
• Small vascular channels / necrosis
• Impaired blood flow
• Cytokines are osteolytic
• Limited osteoblastic capacity of bone

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Treatment of Osteomyelitis

• Drainage
• Debridement
• Obliteration of dead space
• Wound protection
• Antimicrobial therapy
• Usually 4 - 6 weeks IV antibiotics

Pre Debridement
Post Debridement
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Treatment of ostemyelitic infection and
prosthetics

• Two- Stage revision
• Removal of infected implant, tissue, and foreign
  materials
• Culture infection
• Close site
• 4 6 weeks IV antibiotics
• Second surgery for reimplantation
• Preferred method

• Single Stage revision
• Removal of infected implant, tissue, and foreign
  materials
• Culture infection
• remiplantation
• Close site
• antibiotics
• 20 -30 failure rate

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Prevention of ostemyelitic infection and
prosthetics

• Antibiotics prophylaxis
• Skin disinfection
• Good operating discipline
• Ultraviolet irradiation
• Charcoal filtration
• Impregnated PMMA
• Antibiotic coating of prosthetics

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Silver as an antibiotic agent in vivo
applications

• Used for decades in medicine
• Biocidal effects at concentrations as low as 1.24
  micrograms / milliliter (MacKeen, 1987)
• Biocidal effect proportional to local ionic
  concentration
• Distributed throughout entire human body
• Toxic at gt0.35 milligrams / day
• Excreted at rate of 3.97 milligrams / day

Native elemental Silver
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Silver as an antibiotic agent

• High, millimolar, concentration inhibit cellular
  enzymatic activities
• Low concentration inhibits cellular membrane
• Disrupts sodium gradient
• Causes leaking of hydrogen atoms across membrane
• Resistance?
• Silver ion pump on membrane surface
• Small periplasmic silver-binding protein
• Genetically engineered resistant bacteria
• Bacterial exposure to silver for 4 billion years
• No wide spread resistance reported in humans

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Silver ion and usesconstraint criteria

• Delivered to site of infection in an ionic form
• 1.24 micrograms / milliliter lt Local
  concentration lt 30 micrograms / milliliter
• Serum silver levels less than 0.3 micrograms /
  milliliter
• Lifetime, 70 years, must not exceed 8.95 grams

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Silver ion and uses

• Topical for burn patients
• Silver coating for suture material
• Silver coated bladder catheters
• Silver is only effective in ionic form

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Silver Electrically stimulated ionization

• Implant to be coated with silver metal
• Implant needs a source of electrical current-
  allowing for silver ion formation

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Silver Electric

• Silver
• How much needed?
• 50 ppm kills most bacteria
• 1 cm penetration in Agar
• How long needed?
• Conventional therapy 4-6 weeks with

• Electric
• How much?
• Cell can withstand 20uA
• 4.02 ug/ hr of silver will be liberated per
  micro-ampere of current applied to silver
• How long?
• Until infection eradication blood culture
• 4-6 weeks with conventional antibiotics

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Hip Design
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Fixation Fastener Design
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Our Configuration
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Electrical Current

• Internal Source
• Pacemaker battery with leads
• How many volts? 1.3 2 volts
• Battery placement within implant
• Screw cap for hollow end of implant
• Distal end of hip
• Battery life dependant on rate of discharge
• 24 week with Energizer 337
• On/ Off signal? Magnetic
• Feasibility of lead placement IE Dept.

• External Source
• Silver wires with Teflon coating
• Drill holes within bone for lead attachment
• Shearing of leads with bone placement? IE Dept.
• Feasibility of lead placement IE Dept.
• Battery external
• How many volts? 1.3 2 volts

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Silver Coating

• Too Thick
• Toxicity?
• 4- 8 grams IV
• LD50 2 grams IV for cells
• 25 mg / Kg IV Death
• Cell toxicity 30 ug/ml
• 8.95 g lifetime exposure
• Shear forces
• Bone Cortical 50106 N/M2 shear force
• Silver Shear much lower?
• Feasibility and clean up of flaking IE Dept.

• Too Thin
• How many ions?
• 1.93 µg/ ml will decrease bacterial survival by
  10 fold within 13 min
• 24 week ion generation
• 0.0162 grams minimum
• Rate of ion creation?
• 4.02 ug/ hr of silver will be liberated per
  micro-ampere of current applied to silver

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Laboratory Test results

• Materials
• Stainless
• Titanium
• Copper
• Gold
• Silver
• Cadmium
• Nickel
• Bacteria
• Staphacoccus
• Enterococus
• Pseudomonas
• E. Coli
• MRSA
• Fungi
• Candida Albicans

• Resistors
• None
• 3.01 M?
• 1.5 M?
• 150 k?
• 75 k?
• Producing currents
• 0 µA
• 0.5 µA
• 1.0 µA
• 10.0 µA
• 20.0 µA

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Laboratory Test results
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Copper results - Staph







Staph Control
Staph 0.5uA Circuit
Staph 1.0uA Circuit
Staph 20uA Circuit
Staph 10uA Circuit
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Copper results - Ecoli





Ecoli Control
Ecoli 0.5uA Circuit
Ecoli 1.0uA Circuit
Ecoli 10uA Circuit
Ecoli 20uA Circuit
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Copper results - Enterococcus





Enterococcus Control
Enterococcus 0.5uA Circuit
Enterococcus 1.0uA Circuit
Enterococcus 10uA Circuit
Enterococcus 20uA Circuit
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Copper results - Pseudomonas




Pseudomonas Control
Pseudomonas 0.5uA Circuit
Pseudomonas 1.0uA Circuit
Pseudomonas 10uA Circuit
Pseudomonas 20uA Circuit
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Copper results - MRSA


MRSA Control
MRSA 0.5uA Circuit
MRSA 1.0uA Circuit
MRSA10uA Circuit
MRSA 20uA Circuit
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Silver results - Staph











Staph Control
Staph 0.5uA Circuit
Staph 1.0uA Circuit

Staph 10uA Circuit
Staph 20uA Circuit
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Silver results - Ecoli


Ecoli Control
Ecoli 0.5uA Circuit
Ecoli 1.0uA Circuit
Ecoli 10uA Circuit
Ecoli 20uA Circuit
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Silver results - Enterococcus





Enterococcus Control
Enterococcus 0.5uA Circuit
Enterococcus 1.0uA Circuit
Enterococcus 10uA Circuit
Enterococcus 20uA Circuit
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Silver results - Pseudomonas




Pseudomonas Control
Pseudomonas 0.5uA Circuit
Pseudomonas 1.0uA Circuit
Pseudomonas 10uA Circuit
Pseudomonas 20uA Circuit
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Silver results - MRSA


MRSA Control
MRSA 0.5uA Circuit
MRSA 1.0uA Circuit
MRSA10uA Circuit
MRSA 20uA Circuit
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Gold - Results


Ecoli 0.5uA circuit
MRSA 20uA circuit
Pseudomonas 1uA circuit
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Titanium - Results


Enterococcus 10uA circuit
Staph Control
MRSA 0.5uA circuit
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Stainless Steel (316L)- Results


Staph 0.5uA circuit
Pseudomonas 1uA circuit
Ecoli 10ua circuit
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3D Testing
Bell setup and top inhibition ring
Bell inhibition full thickness
Bell inhibition full thickness and
circumferential
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Rapid and Complete Kill of All Known Bacteria and
Fungi

• System is controllable and predictable
• System allows large quantity of silver ions to be
  directed at targeted fungal, bacterial or viral
  presence
• System provides long term microbe free
  environment (years instead of days or weeks)

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Control and Predictability

• Using power stimulated silver (or other
  bactericidal metals) to eliminate infectious
  bacteria

Insulating Material
Silver coated metal
Silver coated metal
Battery
The key to the system is using the bacteria to
carry the electrical load
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This doesnt work
In 1999, R. Wright, at Virginia Tech, tested
silver plated bone fixation plates on 12 canines
and found that this configuration showed no
significant reduction in bacteria. We have shown
that this configuration does not work in a petri
dishand WHY
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Because

• In order to achieve the desired results, the
  bacteria must serve as conductive matter

Bacteria rich environment
Ag
Insulating Material
Silver coated metal
Silver coated metal
Battery
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Hip Design
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Joint Replacement Implants
Hip Replacement
Metal
Metal
Insulator with battery
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External fixation devices
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Laboratory Test results

• Silver consistently produced the largest area of
  inhibition when compared to all other metals

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Laboratory Test results

• Inhibition zones created by silver ions were
  consistent across all bacterial species tested

• Average inhibition distance 21.79 mm
• Standard deviation 4.854 mm

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Laboratory Test results

• Copper produced some inhibition in some species
  of bacteria Gram () strains
• Enterococcus
• Staph
• MRSA

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Cost Opportunity Total Joints

• In 2004, 2 billion was spent to mitigate post
  operative infections caused by foreign hardware.
• - 360M for hips and knees (Darouiche, 2004)
• Direct medical cost per infection 30,000
• In 2004 600,000 procedures put hardware hips and
  knees into the human body (Darouiche, 2004)
• Mitigation cost / procedure for all procedures
  360M / 600K 600 per procedure
• If we can avoid 50 of infections, we could save
  300 per procedure

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Cost Opportunity Fracture Fixation

• In 2004, 2 billion was spent to mitigate post
  operative infections caused by foreign hardware.
  - 1.5 Billion for fracture fixation devices
  (Darouiche, 2004)
• Direct medical cost per infection 15,000
• In 2004 2,000,000 fracture fixation devices were
  implanted into the human body (Darouiche, 2004)
• Mitigation cost/procedure
• 1.5B / 2M 750 per procedure
• If we can avoid 50 of infections, we could save
  350 per procedure

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Increased Cost of Ionizing Silver on an Implant

• Material
• Silver 0.05 / 10 implants
• Battery 1 / implant
• Machining and electronics 10 / implant
• Conservative estimate -- 15 additional
• Current cost 150 for bone screw up to 5,000
  per component for hip and knee

• Current cost ( Wright Medical, 2005)
• Hip example
• Stem 4,800
• Acetabular shell 3,700
• Acetabular Liner 2,000
• Femoral head 3,000
• 3 Screws 150 each
• Total 13,950

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Opportunity

• Total hip system opportunity assuming only 50
  effective system
• Opportunity 300 - 15 285 per operation
• (285 / operation)(600,000 operations / year)
• 171 M potential net savings annually

• Fracture Fixation opportunity assuming only 50
  effective system
• 350 - 15 335 per operation
• (335 / operation)(1,500,000 operations / year)
• 502.5 M potential net savings annually

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Joint Replacement Implants
Hip implant
Metal
Metal
Insulator with battery
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Animal Testing
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Early Rat Testing Results

• 21 animals were used
• 15 survived surgery and two weeks of recovery
• 9 rats were used as control all had
  osteomyelitis
• Of the 6 animals with our device working, 3 were
  staph free

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Our Device in a living rat
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New device designs
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Some early rat testing
Rat tibia in agar with pseudomonas
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Testing Opportunity- Humans

• New spacer
• Only infected patients that need the implant
  removed get a spacer
• New spacer provides antimicrobial weight bearing
  surface
• Potentially clear infection quicker
• Potentially reduce IV antibiotic necessity
• Measure effectiveness Vs. current therapy

• Total knee revision (current)
• Removal of infected implant, tissue, and foreign
  materials
• Culture infection
• Insert spacer device
• Close site
• 4 6 weeks IV antibiotics
• Second surgery for reimplantation

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Applications

• Anywhere that a device can be designed where
  bacteria or fungi can be configured to carry an
  Ag load.
• Medical
• Implants
• External Fixation Devices
• Sterilization
• Commercial
• Critical Surfaces including food preparation,
  pharmaceutical, HVAC

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Ex Vivo Bactericidal Applications

• Use powered (ion release) metals to kill bacteria
  outside the body
• Powered ions to keep sterile air exposed products
  sterile for prolonged time periods
• Potential eradication of bioterrorism agents
• Clothing that is not only clean but is bacteria
  free and remains bacteria free
• Kill bacteria and fungus before they get to us

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Present Prototype Status

• Hands free Bathroom except for door knob
• The scenario is that the hand that touches the
  doorknob that then touches the patients open
  wound could transmit organisms
• (Ginnie Abell RN, BA, CIC - Infection Control
  Today Oct. 05)
• Communal devices - prototype of a Flashlight
• adults and health care workers have a compliance
  rate of only 50 with (hand washing after using
  the restroom)
• (American Journal of Infection Control. 1997
  Oct25(5)424-5 )
• Hotel and restaurant devices - prototype of a TV
  remote
• More than 1 in 3 (39) of employees in small to
  medium firms in the catering industry DO NOT wash
  their hands after visiting the lavatory
• ( British Food Standards Agency nationwide
  survey of food hygiene in the catering industry)

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Our Ex Vivo Configuration
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Other applications commercial surfaces
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Mobile Communications
Motorola Razor V3
Motorola HS850 Headset
Blackberry
Mobile phones used by healthcare professionals
in hospitals are potential sources of infection .
Studies show that up to 40 of the devices carry
bacteria. Mobile phones, which may get
contaminated through the hands and when used
carelessly in the ICU or surgical wards, can act
as a source of infection to patients, they said.
"Moreover, these contaminated mobile phones and
the hands of the healthcare professionals may
also pose a danger in the spread of infection to
the community," reported in the journal Current
Science.
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Doorknobs
Battery assembly
Transparent view of doorknob assembly showing
internal circuit
Styles for hospitals, schools and home.
Exploded view of bacteriacidal doorknob assembly
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Early Lab Testing
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Early Lab Testing
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Early Lab Testing
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Applications

• Medical
• Cancer wards (curtains, serving trays, ..)
• Apparel (surgical clogs, socks, )
• Operating room ventilation systems
• Commercial/government
• Railings, door knobs, ..
• Whole building ventilation systems- antiterrorism
• Hands free bathroom
• Kitchens and food preparation
• Private
• Flashlight, door knob, TV remote, ..

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Product Platform layout
Powered ionization of metallic silver
In Vivo Application
In Vitro Application
Fracture Fixation
Total Joints
Medical
Commercial Government.
Private
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Future Research Issues

• Resorbation
• Quantification of kill rates and thresholds
• Duty cycle
• Biomimetic

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Additional Info - Kill Rates
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Questions?!?