plasma chemistry simulation of surface microdischarge in

Plasma Chemistry Simulation of Surface Microdischarge in Humid Air

for Wound Healing

Yukinori Sakiyama1, David B. Graves1, Marat Orozov1 and Gregor E. Morfill2

1University of California, Berkeley

2Max Planck Institute for Extraterrestrial Physics

Gaseous Electronics Conference 15-18 November, 2011

Salt Lake City

Acknowledgements • Matt Pavlovich(UCB PhD) • Sharmin Karim (UCB, PhD) • Matt Traylor (UCB, Postdoc) • Ting-Ying Chung (UCB, PhD)

NSF NIRT (CTS-0506988) NSF GOALI (DMR-0705953) SRC CAIST FLCC/IMPACT/UC Lam Research Corporation TEL Corporation Max Planck Inst. for Ex. Phys. DOE OFS: LTP Center Nanoscience Fondation, Grenoble, France

• Prof. Gottlieb Oehrlein & colleagues (UMd)

• Colleagues in LTP Science Center

• Prof. Doug Clark, UC Berkeley

R. A. Bryant, et al., Acute and Chronic Wounds (Mosby, Missouri, 2006). G. C. Gurtner., Nature 453 (2008) 314.

Inflammatory phase •  ~48 hours •  bacteria sterilization/debris removal •  blood coagulation

Proliferative phase •  2~10’s days •  blood vessels generation •  collagen deposition from fibroblasts

Remodeling phase •  1 year •  tissue reorganization/realignment •  apoptosis of unnecessary cells

Wound healing process

(Max-Planck) (Drexel Univ)

apoptosis

(TU/e)

(Drexel Univ.)

control

treated

R. A. Bryant, et al., Acute and Chronic Wounds (Mosby, Missouri, 2006). G. C. Gurtner., Nature 453 (2008) 314.

Inflammatory phase •  ~48 hours •  bacteria sterilization/debris removal •  blood coagulation

Proliferative phase •  2~10’s days •  blood vessels generation •  collagen deposition from fibroblasts

Remodeling phase •  1 year •  tissue reorganization/realignment •  apoptosis of unnecessary cells

Known effects of gas plasmas

•  Plasma health care project •  G. Morfill at Max-Planck Institute •  19 PhDs, 11 MDs •  Germany, UK, Russia, Japan, USA

Ongoing wound healing project

J. Heinlin, JDDG 8 (2010) 968, G. Isbary, Br. J. Dermatol. 163 (2010) 78

Phase-I clinical study

Before treatment After 11 treatments Microwave Ar plasma torch

SMD: introduction (1)

copper electrode (powered)!

Insulator!

mesh electrode (grounded)!

microdischarges!

G. Morfill et al., New J. Phys. 11 (2009) 115019 T. Shimizu et al., New J. Phys. 13 (2011) 023026

Sterilization dispenser

SMD

agar plate

Bactericidal effect on agar plate

direct indirect

SMD: introduction (2)

M. Pavlovich et al. (in preparation, 2011)

glass container

copper electrode

SS mesh electrode

glass plate

power supply

Teflon block

Ref. G. Kamgang-Youbi, Appl. Environ. Microbiol. 73 (2007) 4791 K. Oehmigen, Plasma Processes Polym. 7 (2010) 250 M. Traylor et al., J. Phys. D (2011) 472001

PAW = plasma activated water

•  frequency: 10 kHz •  voltage: 10 kV Vpkpk •  power consumption: ~5 W •  distance to sample: ~40 mm •  plasma on: 20 min

•  volume: 10 ml •  medium: distilled water •  storage period: 0-7 days

SMD: introduction (3)

Modeling: 0-D SMD-neutral mass transfer model

SMD Neutral reactor

dpls dgas

Treated surface

Computational domain

zero

flux

zero flux

1j pg

j

pl

p s

s

lR

t dn∂

= − Γ∂ ∑SMD:

Neutral reactor:

1j pg

j

ga

g s

s

aR

t dn∂

= + Γ∂ ∑ ( )plsgas

pgg

gas

as

nD nd

−Γ =

For charged particles:

For neutrals:

0pgΓ =

•  electrons •  ions •  neutrals

•  neutrals

e.g. metal surface with diluted bacteria

10 ns E

Modeling: multiple time-scale phenomena

charge transfer, ion recombination

electron impact reactions

neutral reactions

applied voltage period

gas diffusion

exposure time

100 ns

1 ms

1 s

1 ms

100 s

SMD (electrons, ions, neutrals)

SMD (neutrals)

Neutral reactor (neutrals)

Cycle-averaged reaction rates

SMD (electrons, ions, neutrals)

Simulation procedure

Negative particles: e, O−, O2−, O3

−, O4−, H−, OH−, NO−,N2O−, NO2

−, NO3−

Positive particles: N+, N2+, N3

+, N4+, O+, O2

+, O4+, NO+, N2O+, NO2

+, H+, H2

+, H3+, OH+, H2O+, H3O+

Neutrals: N, N*, N2, N2*, N2**, O, O*, O2, O2*, O3,NO, N2O, NO2, NO3, N2O5, H, H2, OH, H2O, HO2, H2O2, HNO, HNO2, HNO3

Modeling: humid air plasma chemistry at/near R.T.

A. C. Gentile and M. J. Kushner, J. Appl. Phys. 78 (1995) 2074

•  B. Eliasson and U. Kogelschatz, IEEE Trans. Plasma Sci. 19 (1991) 309

•  H.Matzing, Adv. Chem. Phys. 80 (1991) 315

•  W. Sun, et al., J. Appl. Phys. 79 (1996) 3438

•  E. A. Filimonova, et al., J. Phys. D: Appl. Phys. 33 (2000) 1716

•  M.Capitelli et al, "Plasma kinetics in atmospheric gases" (Springer, Berlin 2000)

Model prediction of SMD chemistry

SMD Neutral reactor

zero flux

zero flux

10-8

10-6

10-4

10-2

100

dry30% humidity

N NO

N2O

NO2 NO3

N2O5

O O2*

O3

H2

OH

HO2

H2O2 HNO2

HNO3

Coupling plasma and wound

Wound healed tissue

ROS/RNS

But how to couple plasma model with tissue/wound model??

•  based on Flegg’s model (J.A.Flegg, Bull. Math. Biol. 72 (2010) 1867) •  6-species PDEs in 1-D Cartesian coordinates •  modified parameters and additional terms for plasma treatment

zero

flux

zero flux

x 0 2 1

bacterial load

wounded tissue healed tissue

chemo-attractants

capillary tips

blood vessels

fibroblasts ECM

Major pathways for wound healing

bacteria

oxygen

Hypothesis: Plasma speeds healing by killing bacteria and increasing O2 availability

Wound healing: governing equations (1)

•  Oxygen: c

•  Chemoattractants : a

!c!t

+"i(#Dc"c ) = #k1

1+ kbe+ k2e

$

%&'

()c

k3 + c# k4bc + k5b

!a!t

+"i(#Da"a ) = #k6ab # k7a +k8H (c # cL )H (cH # c )

1+ e

consumption by bacteria

production

chemo-attractants

capillary tips

blood vessels

fibroblasts ECM oxygen

Wound healing: governing equations (2)

•  Capillary tips: n

!n!t

+"i(#Dn"n ) = "i#! nen

(1+ e 2)(1+ a )2"a

$

%&'

()+ a (k9b + k10n ) # n (k11n + k12b)

chemotaxis

chemo-attractants

capillary tips

blood vessels

fibroblasts ECM oxygen

•  Fibroblasts: f

!f!t

+"i(#D f "f ) = "i#! f f

(1+ a )2"a

$

%&

'

() +k16 fc1+ c

#k17 f

2

(1+ c )(1+ e )

chemotaxis

Wound healing: governing equations (3)

chemo-attractants

capillary tips

blood vessels

fibroblasts ECM oxygen

•  Blood vessels: b

13 14 152 2 ( )(1 )(1 )

n k kenb a b e f be a

kt

κ∂ = − ∇ + + −∂ + +

production by capillary tips

•  ECM: e

18 19( )e f ck kt

c e∂ = −∂

deposition

Wound healing: untreated wound

oxygen chemoattractants capillary tips blood vessels fibroblasts ECM

Twice/day plasma treatment

•  99% direct reduction (R)

•  90 min doubling time (kp) 1.0

0.8

0.6

0.4

0.2

0.0

fract

ion

of b

acte

rial l

oad

[-]

3.02.52.01.51.00.50.0time [d]

Time dependent bacterial load

Wound healing: effects of gas plasmas

Wound healed tissue

ROS/RNS

!c!t

+"i(#Dc"c )

= #k1

1+ kbePn + k2e

$

%&'

()c

k3 + c# k4bc + k5b

Oxygen: c

1

1

exp( )1 {exp( ) 1}

nn

n

p

p

PP

PR kR k

tt

−

−=

+ −

Measured antibacterial effects of gas plasmas

direct effect (shorter-term)

> 2-log reduction (99%)

indirect effect (longer-term)

Inhibition of growth (~90min doubling time)

M. Pavlovich, et al. (in preparation) T Nosenko, New J. Phys. 11 (2009) 115013

Wound healing: with plasma treatment

oxygen chemoattractants capillary tips blood vessels fibroblasts ECM

Model prediction of plasma effect on wound healing for infected wound

plasma treatment

untreated

Plasma effects on bacteria: •  99% direct reduction •  90 min doubling time

1.0

0.8

0.6

0.4

0.2

0.0

fracti

on of

bacte

rial lo

ad [

-]

3.02.52.01.51.00.50.0time [d]

1.0

0.8

0.6

0.4

0.2

0.0fract

ion

of w

ound

ed ti

ssue

3.02.52.01.51.00.50.0time [week]

Healing speed: Plasma parameter dependence non-infected wound (1.7 wk) = 1

infected wound (12.5 wk) = 0

Doubling time of bacteria growth [min]

Initi

al B

acte

rial

log

redu

ctio

n

40 60 80 100 120 140

1

1.5

2

2.5

3

3.5

4

0

0.2

0.4

0.6

0.8

1

Concluding remarks

1.  Wound healing model is obviously relatively crude: - e.g. quantities treated as constant parameters are no doubt in reality varying with treatment - small fraction of relevant processes included in model

2.  Effort was made to get consistent parameters from literature

3.  RONS from plasma directly kill surface bacteria but other effects probably important too: - protein/lipid reactions; gene expression - macrophages & inflammation processes…others…

Direct experimental measurements in vivo are crucial for future progress