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IE 497 -- Using Bactericidal Metals for Infections
Richard A. Wysk
And
Thomas Fuller
The Pennsylvania State University
IE497B – Biomedical Engineering
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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
Kentucky Derby winner Barbaro suffers a fractured leg and develops a serious infection after surgery with implanted plate and screws.
Fractured leg
Implants that spawned infection
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Treatment of Osteomyelitis
• Difficult to treat (Bacteria)1. Express receptors /
adhesions allowing adherence to bone or implants
2. Antibiotic resistance
3. Glycocalyx – Slime layer
1999-2000 KUMC Pathology and the University of Kansas,
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Treatment of Osteomyelitis
• Difficult to treat (Bone)1. Bone Microcirculatory
structure sensitive to bacterial toxins
2. Small vascular channels / necrosis
3. Impaired blood flow4. Cytokines are
osteolytic5. 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
Post Debridement
Pre 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 >0.35 milligrams / day
• Excreted at rate of 3.97 milligrams / day
Native elemental Silver
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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
Original implant
Silver Coating Electrical Current source
To Thick To thin Internal External
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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 50*106 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 MΩ– 1.5 MΩ– 150 kΩ– 75 kΩ
• Producing currents:– 0 µA– 0.5 µA– 1.0 µA– 10.0 µA– 20.0 µA
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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 inhibition full thickness and circumferential
Bell setup and top inhibition ring Bell inhibition full thickness
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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), we have developed a device with an on-board power supply, insulating spacer and resistor to eliminate infectious bacteria to constantly release Ag+ into the surrounding environment.
The key to the system is using an insulating spacer and using the bacteria to carry the electrical load
Battery
Silver coated metal
Silver coated metal
Insulating Material
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This doesn’t 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 dish…and WHY
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Because…
• In order to achieve the desired results, the bacteria must serve as conductive matter
Battery
Silver coated metal
Silver coated metal
Insulating Material
Bacteria rich environment Ag+
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So we know that• We get ~20 mm of bactericidal clear
(Anodic) and ~1 mm (Cathodic) for every gap when we put in a device in vivo
Battery
Silver coated metal
Silver coated metal
Insulating Material
Bactericidal zoneBactericidal zone
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Something new
• Multiple panes of Ag and insulators
• Distances between panes
• Organization
Ag-Ag- Ag+Ag+
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Hip Design
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Joint Replacement Implants
Hip Replacement
MetalMetal
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 Averages by Metal
0
5
10
15
20
250 u
A
0.5
uA
1uA
10uA
20uA
Current in uA/ sq cm
Inh
ibit
ion
dis
tan
ce i
n m
m
Silver
Gold
Titanium
Copper
Stainless
Cadmium (Cd)
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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
Silver
0
5
10
15
20
25
30
35
40
0 u
A
0.5
uA
1uA
10uA
20uA
Current in uA / sq cm
Inh
ibit
ion
dis
tan
ce i
n m
m Staph
Ecoli
Enterococcus
Pseudomonas
MRSA
Average
CandidaAlbicans
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Laboratory Test results
• Copper produced some inhibition in some species of bacteria : Gram (+) strains– Enterococcus– Staph– MRSA
Copper
0
5
10
15
20
0 uA
0.5
uA 1uA
10uA
20uA
Current in uA / sq cm
Inh
ibit
ion
dis
tan
ce
in
mm
Staph
Ecoli
Enterococcus
Pseudomonas
MRSA
Average
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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
MetalMetal
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 patient’s 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 Oct;25(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
Silver coating
ConductorBatteryNon-conductive layer/coating
-
+
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Other applications – commercial surfaces
Conductive base
Insulatinglayer
Silver coated surface
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Mobile Communications
BlackberryMotorola Razor V3
Motorola HS850
Headset 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
Transparent view of doorknob
assembly showing internal circuit
Exploded view of bacteriacidal doorknob assembly
Battery assembly
Styles for hospitals, schools and home.
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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
Fracture Fixation
Total Joints
MedicalCommercial & Government.
Private
Powered ionization of metallic silver
In Vivo Application In Vitro Application
Communal devices
Food preparation
Touch surfaces
Biohazard elimination
Public restrooms
Hotel Devices
Food preparation
Private restrooms
Cancer / BMT Wards
Operating rooms
Apparel
Air handling systems
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Future Research Issues
• Resorbation
• Quantification of kill rates and thresholds
• Duty cycle
• Biomimetic
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Additional Info - Kill RatesTime curves
-50
0
50
100
150
200
250
300
350
0 2 4 6 8 10
Tume in Hrs
# o
f C
FU
's *
(10
^6) E. coli control
Staph control
E. coli no resistor
Staph no resistor
E. Coli 3M resistor
Staph 3M resistor
3m resistors
y = 8.3377x2 - 97.468x + 267.22
y = 4.4827x2 - 46.961x + 105.79
0
50
100
150
200
250
300
350
0 2 4 6 8 10
Time in Hrs
CF
U's
* (
10^
6)
E. Coli 3M resistor
Staph 3M resistor
Poly. (E. Coli 3M resistor)
Poly. (Staph 3M resistor)
Time (hr) E.coli S. aureus
0 88 1401 79 1582 79 2323 43 1734 23 2675 44 1656 22 2747 9 2148 3 319
0 106 901 84 1052 75 1133 32 2014 63 2105 55 436 9 587 0 728 0 56
0 321 1401 102 342 115 23 30 04 25 05 4 06 0 07 0 08 0 0
2hr slope Staph 69Ecoli 103
cfu (10E6)
cont
rol
no r
esis
tor
3m r
esis
tor
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Questions?!?