IE 497 -- Using Bactericidal Metals for Infections

Richard A. Wysk

And

Thomas Fuller

The Pennsylvania State University

IE497B – Biomedical Engineering

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

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

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 flow4. Cytokines are

osteolytic5. Limited osteoblastic

capacity of bone

Treatment of Osteomyelitis

• Drainage • Debridement• Obliteration of dead

space• Wound protection• Antimicrobial therapy

– Usually 4 - 6 weeks IV antibiotics

Post Debridement

Pre 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 (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

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 Electrical Current source

To Thick To thin 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 micro-ampere 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 micro-ampere of current applied to silver

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

Copper results - Staph

Staph Control Staph 0.5uA Circuit Staph 1.0uA Circuit

Staph 20uA Circuit Staph 10uA Circuit

Copper results - Ecoli

Ecoli Control Ecoli 0.5uA Circuit Ecoli 1.0uA Circuit

Ecoli 10uA Circuit Ecoli 20uA Circuit

Copper results - Enterococcus

Enterococcus Control Enterococcus 0.5uA Circuit Enterococcus 1.0uA Circuit

Enterococcus 10uA Circuit Enterococcus 20uA Circuit

Copper results - Pseudomonas

Pseudomonas Control Pseudomonas 0.5uA Circuit Pseudomonas 1.0uA Circuit

Pseudomonas 10uA Circuit Pseudomonas 20uA Circuit

Copper results - MRSA

MRSA Control MRSA 0.5uA Circuit MRSA 1.0uA Circuit

MRSA10uA Circuit MRSA 20uA Circuit

Silver results - Staph

Staph Control Staph 0.5uA Circuit Staph 1.0uA Circuit

Staph 10uA Circuit Staph 20uA Circuit

Silver results - Ecoli

Ecoli Control Ecoli 0.5uA Circuit Ecoli 1.0uA Circuit

Ecoli 10uA Circuit Ecoli 20uA Circuit

Silver results - Enterococcus

Enterococcus Control Enterococcus 0.5uA Circuit Enterococcus 1.0uA Circuit

Enterococcus 10uA Circuit Enterococcus 20uA Circuit

Silver results - Pseudomonas

Pseudomonas Control Pseudomonas 0.5uA Circuit Pseudomonas 1.0uA Circuit

Pseudomonas 10uA Circuit Pseudomonas 20uA Circuit

Silver results - MRSA

MRSA Control MRSA 0.5uA Circuit MRSA 1.0uA Circuit

MRSA10uA 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 inhibition full thickness and circumferential

Bell setup and top inhibition ring Bell inhibition full thickness

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), 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

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

Battery

Silver coated metal

Silver coated metal

Insulating Material

Bacteria rich environment Ag+

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

Something new

• Multiple panes of Ag and insulators

• Distances between panes

• Organization

Ag-Ag- Ag+Ag+

Hip Design

Joint Replacement Implants

Hip Replacement

MetalMetal

Insulator with battery

External fixation devices

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)

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

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

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

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

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

MetalMetal

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

• 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

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

ConductorBatteryNon-conductive layer/coating

-

+

Other applications – commercial surfaces

Conductive base

Insulatinglayer

Silver coated surface

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.

Doorknobs

Transparent view of doorknob

assembly showing internal circuit

Exploded view of bacteriacidal doorknob assembly

Battery 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

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

Future Research Issues

• Resorbation

• Quantification of kill rates and thresholds

• Duty cycle

• Biomimetic

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

Questions?!?