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IE 497 -- Using Bactericidal Metals for Infections

This overview examines the use of silver as an antibiotic agent in the treatment of osteomyelitic infections within prosthetics. It includes testing, analysis, and development cost analysis.

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IE 497 -- Using Bactericidal Metals for Infections

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  1. IE 497 -- Using Bactericidal Metals for Infections Richard A. Wysk And Thomas Fuller The Pennsylvania State University IE497B – Biomedical Engineering

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

  3. “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

  4. 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

  5. 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.

  6. 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.

  7. 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,

  8. 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

  9. Drainage Debridement Obliteration of dead space Wound protection Antimicrobial therapy Usually 4 - 6 weeks IV antibiotics Treatment of Osteomyelitis Pre Debridement Post Debridement

  10. 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 Treatment of ostemyelitic infection and prosthetics

  11. Prevention of ostemyelitic infection and prosthetics • Antibiotics prophylaxis • Skin disinfection • Good operating discipline • Ultraviolet irradiation • Charcoal filtration • Impregnated PMMA • Antibiotic coating of prosthetics

  12. 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

  13. Silver ion and uses • Topical for burn patients • Silver coating for suture material • Silver coated bladder catheters • Silver is only effective in ionic form

  14. Silver & Electrically stimulated ionization • Implant to be coated with silver metal • Implant needs a source of electrical current- allowing for silver ion formation

  15. 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 Silver & Electric

  16. Hip Design

  17. Fixation Fastener Design

  18. Our Configuration

  19. 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 Electrical Current

  20. 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 Silver Coating

  21. 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 Laboratory Test results

  22. Copper results - Staph Staph Control Staph 0.5uA Circuit Staph 1.0uA Circuit Staph 20uA Circuit Staph 10uA Circuit

  23. Copper results - Ecoli Ecoli Control Ecoli 0.5uA Circuit Ecoli 1.0uA Circuit Ecoli 10uA Circuit Ecoli 20uA Circuit

  24. Copper results - Enterococcus Enterococcus Control Enterococcus 0.5uA Circuit Enterococcus 1.0uA Circuit Enterococcus 10uA Circuit Enterococcus 20uA Circuit

  25. Copper results - Pseudomonas Pseudomonas Control Pseudomonas 0.5uA Circuit Pseudomonas 1.0uA Circuit Pseudomonas 10uA Circuit Pseudomonas 20uA Circuit

  26. Copper results - MRSA MRSA Control MRSA 0.5uA Circuit MRSA 1.0uA Circuit MRSA10uA Circuit MRSA 20uA Circuit

  27. Silver results - Staph Staph Control Staph 0.5uA Circuit Staph 1.0uA Circuit Staph 10uA Circuit Staph 20uA Circuit

  28. Silver results - Ecoli Ecoli Control Ecoli 0.5uA Circuit Ecoli 1.0uA Circuit Ecoli 10uA Circuit Ecoli 20uA Circuit

  29. Silver results - Enterococcus Enterococcus Control Enterococcus 0.5uA Circuit Enterococcus 1.0uA Circuit Enterococcus 10uA Circuit Enterococcus 20uA Circuit

  30. Silver results - Pseudomonas Pseudomonas Control Pseudomonas 0.5uA Circuit Pseudomonas 1.0uA Circuit Pseudomonas 10uA Circuit Pseudomonas 20uA Circuit

  31. Silver results - MRSA MRSA Control MRSA 0.5uA Circuit MRSA 1.0uA Circuit MRSA10uA Circuit MRSA 20uA Circuit

  32. Gold - Results Ecoli 0.5uA circuit MRSA 20uA circuit Pseudomonas 1uA circuit

  33. Titanium - Results Enterococcus 10uA circuit Staph Control MRSA 0.5uA circuit

  34. Stainless Steel (316L)- Results Staph 0.5uA circuit Pseudomonas 1uA circuit Ecoli 10ua circuit

  35. 3D Testing Bell setup and top inhibition ring Bell inhibition full thickness Bell inhibition full thickness and circumferential

  36. 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)

  37. 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. Insulating Material Silver coated metal Silver coated metal Battery The key to the system is using an insulating spacer and using the bacteria to carry the electrical load

  38. 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

  39. Bacteria rich environment Ag+ Insulating Material Silver coated metal Silver coated metal Battery Because… • In order to achieve the desired results, the bacteria must serve as conductive matter

  40. So we know that Bactericidal zone Insulating Material Bactericidal zone Silver coated metal Silver coated metal Battery We get ~20 mm of bactericidal clear (Anodic) and ~1 mm (Cathodic) for every gap when we put in a device in vivo

  41. Something new Ag+ Ag- Ag+ Ag- Multiple panes of Ag and insulators Distances between panes Organization

  42. Hip Design

  43. Joint Replacement Implants Hip Replacement Metal Metal Insulator with battery

  44. External fixation devices

  45. Laboratory Test results • Silver consistently produced the largest area of inhibition when compared to all other metals

  46. 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

  47. Laboratory Test results • Copper produced some inhibition in some species of bacteria : Gram (+) strains • Enterococcus • Staph • MRSA

  48. 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

  49. 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

  50. 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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