Biomedical applications of plasmas e stoffels eindhoven university of technology the netherlands
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Biomedical applications of plasmas E. Stoffels, Eindhoven University of Technology The Netherlands.  Plasmas in material processing: t hermal vs. non-thermal  Plasmas in medicine: service: plasma decontamination “spare parts”: plasma coating of implants healing: plasma surgery

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Biomedical applications of plasmas e stoffels eindhoven university of technology the netherlands l.jpg

Biomedical applications of plasmasE. Stoffels, Eindhoven University of TechnologyThe Netherlands

 Plasmas in material processing:

thermal vs. non-thermal

Plasmas in medicine:

service: plasma decontamination

“spare parts”: plasma coating of implants

healing: plasma surgery

 New:

minimum-invasive surgery

plasma-tissue interactions on cellular level


What is plasma l.jpg

+

-

A+, B-, e, radicals

What is plasma?

  • Almost everything!

  • Ionised gas:

    • thermally (fire)

    • electrically (gas discharge)

    • radiatively (ionosphere, interstellar space)

  • Artificial plasmas: generated by electric discharges:


Plasmas in material processing l.jpg
Plasmas in material processing

 Plasmas can perform various surface treatment:

etching - semiconductor elements

deposition - a-Si:H solar cells, hard protective coatings, optically active layers, etc.

cutting, welding, spraying

 Refined treatment is possible with non-thermal plasmas (no heat damage to the surface)

 Also biological materials can be treated!


Thermal fire non thermal vacuum reactor l.jpg
Thermal (fire) Non-thermal(vacuum reactor)


How to obtain non thermal plasmas l.jpg
How to obtain non-thermal plasmas?

 Electric gas discharges: electrons/ions are heated

 In typical high-frequency plasmas only electrons are heated

 No background gas heating when:

electrons/ions in minority

not enough collisions with neutrals

Thermal: gas heating occurs Non-thermal: electrons hot, gas cold


Non equilibrium cases l.jpg
Non-equilibrium cases

low pressure:

low collision frequency of electrons with gas electrons retain high energy, gas remains cold

(typical situation in vacuum reactors)

 short duration of the plasma pulse:

not enough time for gas heating

small size (micro-plasma):

too much energy leaks to outside


Small size plasma l.jpg
Small size plasma

 What is the maximum length scale (L) of a “cold” plasma?

 Electron-induced heating is balanced by thermal conduction losses:

 We allow DT to be at most 10 degrees.

 For helium under typical conditions L 0.2 mm

(in agreement with observations).


Plasma needle l.jpg
“Plasma needle”

 RF applied to a sharp metal pin.

 breakdown obtained at ca. 200 V p-p.

 plasma operates in helium (most readily), argon, nitrogen, hydrogen, AIR (!)



Really cool l.jpg

small size

expansion

Really cool!

Temperature measurements using Optical Emission Spectroscopy (N2 bands)

using thermocouples


Other geometries l.jpg

Ar

Other geometries

 HF plasma pencil (Janca et al. Brno, Czech Republic)

discharge created in a hollow needle/hollow cylinder in argon

various surface treatments

 Micro-hollow cathode discharge (Schoenbach, Norfolk, Virginia; Graves, California, Berkeley)


Slide12 l.jpg

Dielectric/high resistivity material

 Dielectric barrier discharge DBD (e.g. Kogelschatz, ABB Corp. Research; Chang-Jun Liu, Tianjin, China)

UV radiation

gas conversion (e.g. methane)

 Resistive barrier discharge (Laroussi, Old Dominion Univ. Virginia)

bacterial decontamination


Slide13 l.jpg

 Atmospheric pressure plasma jet APPJ (Selwyn, Los Alamos)

radio-frequency (13.56 MHz)

material processing

 One atmosphere uniform glow discharge plasma OAUGDP (Reece Roth et al. Univ. of Tennessee)

kHz frequency range

operates in air

needs cooling

used for sterilisation


Slide14 l.jpg

Plasma sterilisation (medical tools) Alamos)

  • Low temperature needed because of usage of plastic tools.

  • Plasma is non-toxic and efficient (seconds to minutes)

  • Both atmospheric (Reece Roth, Laroussi) and reduced pressure discharges (Moisan) are used.

  • Large-area discharges, AC, radio-frequency and microwave.


Air deconamination l.jpg
Air deconamination Alamos)

  • Removal of bacteria/bacterial spores from ambient air (e.g. anthrax)

  • Protection from biological attacks

  • Example: a gas phase corona reactor design by Birmingham et al. (MesoSystems Technology Inc., Richland)


Water purification l.jpg
Water purification Alamos)

  • Under water corona discharges (e.g. Sunka, Prague, Chech Republic; Van Veldhuizen, Eindhoven, The Netherlands)

  • corona streamers propagate in contaminated liquid

  • not only biological threats can be removed; dangerous chemicals are decomposed.

pulsed corona for water cleaning

(V. Veldhuizen, Eindhoven)


Destroying enemies l.jpg
Destroying enemies Alamos)

  • prokaryotic organisms, not very complicated

  • most of them well-protected by cell wall


Destroying enemies18 l.jpg
Destroying enemies Alamos)

  • Gram positive vs. gram negative

    single plasma membrane double membrane

  • Spore forming (typically more difficult to gram positive) destroy

    bacillus,

    clostridium

  • most of them well-protected by cell wall

endospore

escherichia coli


Slide19 l.jpg

Mechanisms? Alamos)

  • No sophisticated damage needed: necrosis

  • Atomic oxygen vs UV radiation.

  • Typically three phases observed.

  • Moisan and coworkers (Univ. of Montreal) proposed bacterial/spore de-activation mechanisms

Erosion by photodesorption and O radical etching

UV damage to eroded spores

Direct UV absorption and DNA destruction

log(number of survivors)

 1 min 10 min 1 min

exposure time


Chemical effects l.jpg
Chemical effects Alamos)

  • Various chemistries studied

    argon - not very efficient

    N2/O2 (air) - efficient, O radicals present

    O radicals can also penetrate through the membrane and damage the cell interior

    H2O2, CO2- particularly efficient, see Hury et al.

    H2 - efficient, reducing agent.

    Maybe reducing fatty acids to aldehydes and dissolving the membrane?


Decontamination of other surfaces l.jpg
Decontamination of other surfaces? Alamos)

 In vivo dental cavities using plasma needle

 No temperature increase within the tooth

 Mineral matrix intact, tissue-saving method

 Under investigation: decontamination efficiency, penetration depth, surface activation to enhance adhesion of filling

 Pain?

 Others: root

treatment , gingiva

reattachment


Plasma coating l.jpg
Plasma coating Alamos)

 Coating of artificial implants to increase bio-compatibility

 Low-pressure discharges can be used

 Examples:

bone prostheses: diamond-like inert coating on titanium substrate

spraying of hydroxyapatite

micro-patterning of surface to increase cell adhesion


Plasma treatment in vivo l.jpg
Plasma treatment in vivo Alamos)

 Not always non-thermal plasmas are used, sometimes burning is desired

 Techniques already implemented in medicine: electro-surgery and argon plasma coagulation

 Spark erosion of atherosclerotic plaque

 New trends: minimum invasive, tissue saving methods

 Investigation of fine surgery using plasma needle


Slide24 l.jpg

Electric methods in medicine Alamos)

 Electrosurgery: well established technique

 High-frequency (350 kHz) cutting and coagulation:

ERBE

monopolar & bipolar cutting devices

well-reproducible cutting

little adhesion

hemostasis obtained

by controlled coagulation


Slide25 l.jpg

From electricity Alamos)to plasma

First beneficial plasma-tissue interaction

* non contact

* self-limiting desiccation and coagulation (plasma stops when the area is dry)

* no carbonization

* can be applied internally

* good post-operative recovery

 Argon plasma coagulation


Slide26 l.jpg

An APC device in action Alamos)

Example: treatment of hyperplasia of the nasal concha

After APC treatment 10 days later


Spark erosion l.jpg
Spark erosion Alamos)

Plaque is vaporized by electric pulses, 250 kHz, 1200 V, 100 W. Restenosis in rabbits is limited. So far not applied to humans.

A diseased artery Plasma-produced crater

(cross-section): (lipid ablation):

  • Developed by dr. C.J. Slager (Erasmus Univ. Rotterdam)


Slide28 l.jpg

A few words about safety Alamos)

Nerve stimulation

by electric currents

Effects of heat: hyperthermia causes cell death (> 43o C)


Plasma needle on tissues l.jpg
Plasma needle on tissues Alamos)

(a) Low-power regime: no thermal damage, possibility of refined action.

(b) High-power regime: denaturation of proteins, carbonisation after long exposure.

Possibility of fine surgery must be investigated on cellular level!


Next step eukaryotic cells l.jpg
Next step: eukaryotic cells Alamos)

 Much more complicated structures

 More interactions/effects possible

 For the sake of plasma surgery, understanding plasma-induced effects on cellular level is necessary


Plasma cell interactions l.jpg
Plasma-cell interactions Alamos)

  • Cell removal:

    • “coarse destruction” - necrosis (damage to the membrane) caused e.g. by chemicals.

    • “fine works” - programmed cell death (apoptosis)


Apoptosis l.jpg
Apoptosis Alamos)

  • Moderate damage to the cell, without affecting the membrane integrity. The cell shrinks, DNA in the nucleus condenses.

  • Cell disappears without infection, as desired in fine surgery.


Cho k1 cells in culture l.jpg
CHO-K1 cells in culture Alamos)

  • CHO-K1 cells (Chinese hamster ovary) , fibroblasts

  • Plasma treatment followed by viability assays

  • Fluorescent staining and observation under confocal fluorescence microscope

    Cell Tracker Green (CTG): stains living cells green

    Propidium Iodide (PI): stains dead cells red,

    allows to resolve DNA/RNA distribution in the cell


Healthy cells l.jpg
Healthy cells: Alamos)

 To study long term effects cells are cultured after plasma treatment

 Cells are fixed and stained with PI to detect apoptosis

 Intact nuclei stained by PI


General features of plasma treatment l.jpg
General features of plasma treatment Alamos)

 High precision: influenced cells are strictly localised)

detachment

50 mm

alive dead


Plasma treated cells l.jpg
Plasma treated cells Alamos)

Example of apoptotic cells After plasma treatment


Slide37 l.jpg

Plasma treated cells: dead cells Alamos)

Even dead cells retain the integrity!

DNA damage and condensation (other than in apoptosis)


Slide38 l.jpg

Cell detachment Alamos)

Instantaneous effect of plasma treatment

 Cells round up and detach from other cells and can be removed

 Better (faster)

than apoptosis?


Slide39 l.jpg

Long term effects Alamos)

Detached cells reattach after ca 1 hour, their viability is demonstrated

15 min

control

4 hours

1 hour


What causes cell detachment l.jpg

Ca Alamos)

Ca

Ca

NH2

membrane

COOH

cytoskeleton

What causes cell detachment?

 cell adhesion molecules (CAMs) - trans-membrane glycoproteins

 Ca2+ dependent adhesion:

cadherins

 Detract Ca and cause

cadherin to disintegrate?

(only charging)

 Destroy the cadherin


Summary l.jpg
Summary Alamos)

  • Plasma technology finds many medical applications.

  • Many atmospheric sources have been developed.

  • Plasma de-contamination is widely studied.

  • Plasma needle can be applied to organic materials without thermal damage.

    Questions

  • Can plasmas perform fine surgery?

  • Is cell detachment valid in tissue environment

in vivo tests


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