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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
