BE 400 Infections in Medical Devices Exam 3

Periprosthetic Joint Infection (PJI)

devastating outcome of total joint anthroplasty

Effects of PJI

• increased patient morbidity

• increased costs to the healthcare system

• difficult to diagnose

Example of PJI

• loosening of knee replacement due to biofilm

• tissue infected and bone is necrotic

• antibiotic loaded cement spacer placed

• patient cannot walk so they lose bone mass

• next implant(s) more likely to be complicated, often leads to amputation

How do bacteria resist decontamination?

by forming biofilms on implants

Which most contributes to the infection of A. baumani on a titanium device?

mature biofilm stage

Commercially pure titanium (cpTi)

• one of the most used biomaterials for orthopedic and dental applications

• good mechanical strength and biocompatibility

• protected by oxide film

Does an anodic reaction build or destroy oxide layer?

builds

Open circuit potential (OCP)

• electrochemical reactions are at steady state

• rate of anodic half cell reactions equal the rate of cathodic half cell reactions

titanium anodic reaction

titanium oxidation

titanium cathodic reduction

oxygen and water reduction

How does environment affect OCP?

changes it

OCP of titanium

-0.300 V

Faradaic

transfer of charge

non-Faradaic

accumulation of charge

How is electrochemistry analyzed?

electrochemical impedance spectroscopy (EIS)

Circuit element representation for Faradaic

resistor, charge just flows through with some resistance

Circuit element representation for non-Faradaic

capacitor, accumulates charge before passing

Pourbaix Diagram

thermodynamic predictions of when corrosion will occur

Alternative name for Pourbaix diagram

potential pH diagram

What is shown on a Pourbaix diagram?

the reaction and reaction products that will be present at equilibrium

Potentiodynamic polarization scan

shows the actual electrochemistry

What happens when the titanium reaction becomes diffusion dependent?

• reaction is essentially at its peak and relies on the diffusion of reactants

• this is when water reduction begins

What do we make when we polarize titanium cathodically?

• 4OH- from oxygen reduction

• 2OH- and H2(g) from water reduction

How do the products of titanium polarization impact bacteria growth?

• OH- increases pH, which creates an environment bacteria don’t want to grow in

• H2 has can mechanically disrupt the surface of a biofilm, kind of like carbonation

Oxygen reducation

O2+H2O + 4e- → 4OH-

Water reduction

2H2O+2e- → H2+ 2OH-

Cathodic voltage controlled electrical stimulation (CVCES)

• by controlling the voltage, we can determine the electrochemical reactions on the surface of the implant

What is the rate of reactions in CVCES controlled by?

• current

• current fluctuates based on what is required to maintain the voltage

Mechanism of action CVCES

More basic pH and formation of H2 gas

Which analysis method helps understand the behavior of titanium in electrochemical environments?

electrochemical impedance spectroscopy

What can be inferred about the role of electron transfer in reduction reactions

it is essential for facilitating the conversion of O+ to OH-

working electrode

maintains potential with respect to the counter electrode

counter/return electrode

responsible for current flow back to working electrode

parts of three electrode configuration for EIS measurments

• working electrode

• counter electrode

• reference electrode

What is CVCES dependent on?

time and magnitude of treatment

Why is there a difference between -1.5 V CVCES and -1.8 V CVCES?

• -1.5 V involves just oxygen reduction

• -1.8 involves both oxygen and water reduction

Results of CVCES prevention with gentamycin

~8 log reductions from all conditions for both -1.0 V and -1.5 volts with gentamycin

Why are antibiotics and CVCES synergistic?

• CVCES alters the transmembrane potential (difference of charge between environment and inside of bacteria)

• different transmembrane potential leads to increased antibiotic uptake

How effective is CVCES as a treatment?

• 1 log reduction from 1 hour of treatment

• because it goes from 10^6 to 10^5, this is a large decrease

Why is CVCES promising?

results show it can be effective at both preventing and treating infection

current controlled electrical stimulation

show an increase in pH at the cathode and decrease at the anode

Difference between current controlled electrical stimulation and CVCES

With current controlled electrical stimulation, there’s no control over the voltage or electrochemical reactions on the surface

Mechanism of action for electrical stimulation

alkaline from oxygen and water reduction impacts bacterial viability (pH kills bacteria)

electrical stimulation impact on cellular bioenergetics

• ATP is produced because of proton motive force (pH+ electrostatic charge gradients)

• charge regulation changes surface pH, and ultimately proton motive force

• when we apply negative potential to titanium, increases membrane potential

• if proton motive force is more positive (increased pH + increased membrane potential) then protons will move out instead of into cell, so no ATP produced

Why does CVCES work?

• effects on bioenergetics

• Formation of OH- and pH increase

• Formation of H2 bubbles as a mechanical disrupter

potential advantages of electrical stimulation

• osseointegration

• CT shows woven bone formation around an implant showing that it promotes, maintains or enhances osseointegration

potential disadvantage of electrical stimulation

• tissue damage

• This is magnitude and time dependent

How might electrical stimulation cause tissue damage?

• hydrogen gas in the body can have negative impacts

• impact of pH change on human tissue

• electricity=heat, potential for burning

Applications of electrical stimulation for infection control

• orthopedic implants

• wound infections and skin ulcers

• urinary tract and catheter associated infections

• respiratory tract and lung infections

• treating osteomyelitis

Role of electrical stimulation in chronic wound treatment

antimicrobial effects: can disrupt biofilms, increasing bacterial susceptibility to antibiotics and immune attack

enhanced wound healing: has been shown to promote fibroblast proliferation, collagen synthesis, and angiogenesis, accelerating tissue repair

types of electrical stimulation used for chronic wounds and skin ulcers

• high-voltage pulsed current

• direct current

• pulsed electromagnetic fields

high-voltage pulsed current (HVPC)

enhances wound healing and bacterial clearance

direct current (used for wounds)

creates an electrochemical reaction that generates antimicrobial agents (e.g. hydrogen peroxide)

pulsed electromagnetic fields (PEMFs) and wound closure

shown to improve wound closure rates

electrical stimulation strategies for preventing/treating catheter associated UTIs

• disrupting biofilm formation

• electrochemical generation of antimicrobial agents

• enhancing antibiotic efficiency

• electrically conductive coatings for catheters are in development

• stimulation catheter treatments could reduce infection rates

electrical stimulation potential in respiratory infections

• electrical stimulation of lung tissue or airway surfaces may disrupt biofilms and enhance antibiotic penetration

• research is ongoing into how electrical stimulation could be applied through inhalable electrodes or airway-targeted therapies

Electrical stimulation-based dressings

• some bioelectric dressings generate a weak electric field that kills bacteria and enhances tissue repair

• Ex. silver-based electrical stimulation dressing that use microcurrents to generate antimicrobial effects

Treatment of osteomyelitis using electrical stimulation

• electrochemical therapy can help disrupt biofilms in bone infections

• electrical stimulation has been explored in combination with antibiotic-loaded bone scaffolds to improve infection control and bone regeneration

future directions of electrical stimulation

• miniaturized, implantable electrical stimulation devices for infection control

• smart bandages with integrated electrical stimulation for real-time bacterial detection and treatment

• personalized electrical stimulation therapy based on biofilm composition

How does ultrasound work?

• mechanical sound wave that propagates through a medium

• creates alternating compressions and rarefactions

How is ultrasound traditionally used?

as an imaging modality

What does the term ultrasound actually refer to?

sound waves with frequencies above 20 kHz, beyond human hearing

Common frequencies for diagnostic and therapeutic ultrasound

Diagnostic: 1-15 MHz

Therapeutic: 20 kHz-3MHz

What are 1-15 MHz ultrasound waves used for?

• diagnostic ultrasound

• high resolution makes them good for imaging

What are 20kHz-3MHz ultrasound waves good for?

• therapeutic ultrasound

• used for treatments

• tissue stimulation and bacterial disruption

Piezoelectric Effect

• transducer conducts an electrical signal through probe (crystals)

• crystals vibrate and create mechanical waves that transfer energy into human body

Amplitude of ultrasound depends on

• acoustical power used to generate the mechanical compression wave

• medium through which it is transmitted

Compression and rarefaction of molecules is represented as a _______

sine wave

What does the amplitude of ultrasound waves represent?

intensity of the energy in the signal

What are the options for an ultrasound wave when it encounters different tissues?

• transmit: pass through the medium

• reflect-bounce back at interfaces, forming echoes in imaging

• absorb- convert into heat, used in therapeutic applications

• scatter- spread out, especially in rough or non-homogenous structures

Propagation speed

the speed at which the waves travels, which depends on the medium

Propagation speed of ultrasound in air

~330 m/s

Propagation speed of ultrasound in water

~1500 m/s

Propagation speed of ultrasound in bone

~3000-4000 m/s

What is the amount of reflection and transmission dependent on/

acoustic impedance (Z) of the materials

Acoustic impedance equation

Z=ρc

What does ρ and c represent in acoustic impedance formula?

p is the tissue density and c is the speed of sound in that tissue

High impedance mismatch

• like bone and soft tissue

• more reflection

low impedance mismatch

• like similar soft tissues

• more transmission

high frequency ultrasound traits

• better resolution

• lower penetration

frequency

the number of wave cycles per second (Hz)

lower frequency ultrasound traits

• deeper penetration

• lower resolution

Effects of density of wave propagation

denser materials=faster wave propagation

Wavelength

the distance between two consecutive peaks of the wave

How are frequency and wavelength related?

λ=c/f

Diagnostic ultrasound

• uses high-frequency sound waves to create images of internal structures

• commonly used in pregnancy, cardiac assessment, and tumor detection

Therapeutic Ultrasound types

• consistent ultrasound

• low-intensity pulsed ultrasound(LIPUS)

• high-density focused ultrasound (HIFU)

• sonoporation

Types of effects of ultrasound on biological systems

• thermal

• non-thermal

Non-thermal effects

• cavitation(bubble formation

• acoustic streaming

• mechanical stress and shear forces

Continuous ultrasound waves

• ultrasound waves are delivered without interruption

• produces thermal effect, increasing tissue temperature

Frequency of consistent ultrasound

1-3MHz

Biological effects of consistent ultrasound

• increases blood flow and oxygenation to tissues

• enhances tissue elasticity and reduces muscle stiffness

• accelerates wound and soft tissue healing

• can kill bacteria and biofilms via hyperthermia

Deep tissue heating

used in physical therapy to treat muscle strains, tendon injuries, and joint pain

Chronic wound healing

enhances collagen synthesis and tissue regeneration

biofilm disruption and infection control

used experimentally to weaken bacterial biofilms

consistent ultrasound applications

• deep tissue heating

• chronic wound healing

• biofilm disruption and infection control

HIFU

• uses high-intensity, concentrated ultrasound energy at a single point

• generates extreme heat (up to 85 degrees C) to destroy targeted tissue

• Like using a magnifying glass and the sun on a leaf to burn a hole

HIFU frequency

0.8-3 MHz

Biological effects of HIFU

• thermal ablation (kills infected or cancerous tissues)

• breaks down bacterial biofilms and destroys pathogens

• used for deep-tissue infections and tumor ablation

• individual beams do not have effect, but focal point does

mechanism of thermal ultrasound

• molecular vibration and friction

• increased temperature

• improved blood flow and oxygenation

• enhanced permeability