ISE 789 -- Using Bactericidal
Metals for Infections
Richard A. Wysk
And
Thomas Fuller
Overview
•
•
•
•
•
•
•
Background
Osteomyelitic infections within prosthetics
Silver as an antibiotic agent
Silver Design
Testing & Analysis
Development Cost Analysis
Conclusions
“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
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
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.
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.
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,
Treatment of Osteomyelitis
•
Difficult to treat
(Bone)
1. Bone Microcirculatory
structure sensitive to
bacterial toxins
2. Small vascular
channels / necrosis
3. Impaired blood flow
4. Cytokines are
osteolytic
5. Limited osteoblastic
capacity of bone
Treatment of Osteomyelitis
• Drainage
• Debridement
• Obliteration of dead
space
• Wound protection
• Antimicrobial therapy
Pre Debridement
– Usually 4 - 6 weeks IV
antibiotics
Post Debridement
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
Prevention of ostemyelitic infection
and prosthetics
• Antibiotics prophylaxis
• Skin disinfection
• Good operating
discipline
• Ultraviolet irradiation
• Charcoal filtration
• Impregnated PMMA
• Antibiotic coating of
prosthetics
Silver as an antibiotic agent – in
vivo applications
• Used for decades in medicine
• Biocidal effects at
concentrations as low as 1.24
micrograms / milliliter
• 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
(MacKeen, 1987)
Native elemental Silver
Silver ion and uses
• Topical for burn
patients
• Silver coating for
suture material
• Silver coated
bladder catheters
• Silver is only
effective in ionic
form
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
To Thick
To thin
Electrical Current source
Internal
External
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 microampere of current applied
to silver
– How long?
• Until infection eradication
– blood culture
• 4-6 weeks with
conventional antibiotics
Hip Design
Fixation Fastener Design
Our Configuration
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
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 microampere of current applied
to silver
Laboratory Test results
•
Materials:
–
–
–
–
–
–
–
•
Bacteria
–
–
–
–
–
•
Stainless
Titanium
Copper
Gold
Silver
Cadmium
Nickel
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
Copper results - Staph
Staph Control
Staph 0.5uA Circuit
Staph 20uA Circuit
Staph 1.0uA Circuit
Staph 10uA Circuit
Copper results - Ecoli
Ecoli Control
Ecoli 0.5uA Circuit
Ecoli 10uA Circuit
Ecoli 1.0uA Circuit
Ecoli 20uA Circuit
Copper results - Enterococcus
Enterococcus Control
Enterococcus 10uA Circuit
Enterococcus 0.5uA Circuit
Enterococcus 1.0uA Circ
Enterococcus 20uA Circuit
Copper results - Pseudomonas
Pseudomonas Control
Pseudomonas 10uA Circuit
Pseudomonas 0.5uA Circuit
Pseudomonas 1.0uA Circ
Pseudomonas 20uA Circuit
Copper results - MRSA
MRSA Control
MRSA 0.5uA Circuit
MRSA10uA Circuit
MRSA 1.0uA Circuit
MRSA 20uA Circuit
Silver results - Staph
Staph Control
Staph 0.5uA Circuit
Staph 10uA Circuit
Staph 1.0uA Circuit
Staph 20uA Circuit
Silver results - Ecoli
Ecoli Control
Ecoli 0.5uA Circuit
Ecoli 10uA Circuit
Ecoli 1.0uA Circuit
Ecoli 20uA Circuit
Silver results - Enterococcus
Enterococcus Control
Enterococcus 10uA Circuit
Enterococcus 0.5uA Circuit
Enterococcus 1.0uA Circ
Enterococcus 20uA Circuit
Silver results - Pseudomonas
Pseudomonas Control
Pseudomonas 0.5uA Circuit
Pseudomonas 10uA Circuit
Pseudomonas 1.0uA Circuit
Pseudomonas 20uA Circuit
Silver results - MRSA
MRSA Control
MRSA 0.5uA Circuit
MRSA10uA Circuit
MRSA 1.0uA Circuit
MRSA 20uA Circuit
Gold - Results
Ecoli 0.5uA circuit
MRSA 20uA circuit
Pseudomonas 1uA circuit
Titanium - Results
Enterococcus 10uA circuit
Staph Control
MRSA 0.5uA circuit
Stainless Steel (316L)- Results
Staph 0.5uA circuit
Pseudomonas 1uA circuit
Ecoli 10ua circuit
3D Testing
Bell setup and top inhibition ring
Bell inhibition full thickness
Bell inhibition full thickness and circumferential
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)
Control and Predictability
• Using power stimulated silver (or other
bactericidal metals) to eliminate infectious
bacteria
Insulating Material
Silver coated
metal
Battery
Silver coated
metal
The key to the system is using the bacteria to carry
the electrical load
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
Because…
• In order to achieve the desired results, the
bacteria must serve as conductive matter
Ag+
Bacteria rich environment
Insulating Material
Silver coated
metal
Battery
Silver coated
metal
Hip Design
Joint Replacement Implants
Hip Replacement
Metal
Metal
Insulator with battery
External fixation devices
Laboratory Test results
25
Silver
20
Gold
15
Titanium
10
Copper
Stainless
5
Cadmium (Cd)
Current in uA/ sq cm
20uA
10uA
1uA
0.5 uA
0
0 uA
Inhibition distance in mm
• Silver consistently produced
the largest area of inhibition
when compared to all other
Averages by Metal
metals
Laboratory Test results
• Inhibition zones created by silver ions
were consistent across all bacterial
species tested
Silver
40
Ecoli
35
Enterococcus
30
25
Pseudomonas
20
MRSA
15
Average
10
Candida
Albicans
5
Current in uA / sq cm
20uA
10uA
1uA
0.5 uA
0
0 uA
• Standard
deviation =
4.854 mm
Staph
Inhibition distance in mm
• Average
inhibition
distance =
21.79 mm
Laboratory Test results
20
15
Staph
Ecoli
10
Enterococcus
5
Pseudomonas
0
20uA
10uA
1uA
0.5 uA
MRSA
0 uA
– Enterococcus
– Staph
– MRSA
Copper
Inhibition distance in
mm
• Copper
produced some
inhibition in
some species of
bacteria : Gram
(+) strains
Current in uA / sq cm
Average
Cost Opportunity – Total Joints
• In 2004, $2 billion was spent to mitigate post
operative infections caused by foreign hardware.
- $360M for hips and knees
• Direct medical cost per infection $30,000
• In 2004; 600,000 procedures put hardware hips
and knees into the human body
• Mitigation cost / procedure for all procedures =
$360M / 600K = $600 per procedure
(Darouiche, 2004)
(Darouiche, 2004)
– If we can avoid 50% of infections, we could save
$300 per procedure
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
• Direct medical cost per infection $15,000
• In 2004; 2,000,000 fracture fixation devices were
implanted into the human body
• Mitigation cost/procedure =
$1.5B / 2M = $750 per procedure
(Darouiche, 2004)
(Darouiche, 2004)
– If we can avoid 50% of infections, we could save
$350 per procedure
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
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
Joint Replacement
Implants
Hip implant
Metal
Metal
Insulator with battery
Animal Testing
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
Our Device in a living rat
New device designs
Some early rat testing
Rat tibia in agar with pseudomonas
Testing Opportunity- Humans
•
• Total knee revision
(current)
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
– Removal of infected
implant, tissue, and foreign
materials
– Culture infection
– Insert spacer device
• Measure effectiveness
– Close site
Vs. current therapy
– 4 – 6 weeks IV antibiotics
– Second surgery for
reimplantation
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
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
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)
Our Ex Vivo Configuration
Silver coating
+
Non-conductive layer/coating
Conductor
Battery
Other applications – commercial
surfaces
Silver coated
surface
Insulating
layer
Conductive
base
Mobile Communications
Blackberry
Motorola
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.
Doorknobs
Battery
assembly
Transparent view of doorknob assembly
showing internal circuit
Exploded view of bacteriacidal
doorknob assembly
Styles for
hospitals,
schools and
home.
Early Lab Testing
Early Lab Testing
Early Lab Testing
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, ..
Product Platform layout
Powered ionization
of metallic silver
In Vivo Application
Fracture
Fixation
Total
Joints
In Vitro Application
Medical
Cancer /
BMT Wards
Operating
rooms
Apparel
Air handling
systems
Commercial &
Government.
Communal
devices
Food
preparation
Touch
surfaces
Biohazard
elimination
Public
restrooms
Private
Hotel
Devices
Food
preparation
Private
restrooms
Future Research Issues
• Resorbation
• Quantification of
kill rates and
thresholds
• Duty cycle
• Biomimetic
Additional Info - Kill Rates
350
300
250
# of CFU's * (10^6)
Time (hr)
0
1
2
3
4
5
6
7
8
0
1
2
3
4
5
6
7
8
0
1
2
3
4
5
6
7
8
cfu (10E6)
E.coli
S. aureus
88
140
79
158
79
232
43
173
23
267
44
165
22
274
9
214
3
319
106
90
84
105
75
113
32
201
63
210
55
43
9
58
0
72
0
56
321
140
102
34
115
2
30
0
25
0
4
0
0
0
0
0
0
0
E. coli control
200
Staph control
E. coli no resistor
150
Staph no resistor
E. Coli 3M resistor
100
Staph 3M resistor
50
0
0
2
4
6
8
10
-50
Tume in Hrs
3m resistors
350
E. Coli 3M resistor
300
Staph 3M resistor
250
CFU's * (10^6)
3m resistor
no resistor
control
Time curves
Poly. (E. Coli 3M resistor)
200
Poly. (Staph 3M resistor)
150
y = 8.3377x 2 - 97.468x + 267.22
100
y = 4.4827x 2 - 46.961x + 105.79
Staph
Ecoli
2hr slope
69
103
50
0
0
2
4
6
Time in Hrs
8
10
Questions?!?