biomedical applications of ambient gas plasma: the confluence of
TRANSCRIPT
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Biomedical Applications of Ambient Gas Plasma: The Confluence of
Redox Biology and Plasma Science
David B. GravesUniversity of California, Berkeley
Chemical Engineering Departmentand the
Michigan Institute for Plasma Science and EngineeringUniversity of Michigan
September 18, 2012
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Acknowledgements•Yuki Sakiyama (UCB Res. Assoc.)•H.-W. Chang (Ph.D. candidate, National Taiwan University, UCB visitor)•Matt Pavlovich (UCB PhD)•Sharmin Karim (UCB PhD)•Matt Traylor (former UCB postdoc)
•John Coburn (UCB, ret. visitor)•Dave Fraser (UCB, ret. visitor)•Harold Winters (UCB, ret. visitor)
NSF NIRT (CTS-0506988)NSF GOALI (DMR-0705953)Semiconductor Research CorporationHitachi CorporationDOE OFS; Plasma Science CenterMPE, Garching, GermanyLam Research Corporation
•Prof. Gottlieb Oehrlein (UMd)•Prof. Doug Clark (UCB)
• Prof. Greg Morfill (MPE, Garching, Germany)•Prof. Volker Schultz-von der Gathen(Ruhr Univ. Bochum, Germany)•Dr. Tetsuji Shimizu (MPE, Germany)•Dr. Jim Barthel (Moffitt Cancer Center, Tampa)•Dr. Eva Stoffels (Eindhoven Univ.)•Prof. John Goree (U Iowa)•Prof. Mark Kushner (U Mich.)
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Natural Ionized Gas Plasmas
Lightning Solar Corona
‘Whirlpool galaxy’ M51;plasma emission andmagnetic field lines
Aurora
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Tokamaks – Plasma Fusion
ITER: International Thermonuclear Experimental Reactor: plasma fusionfor electric power generation
Notice scale!
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‘Low Temperature” Plasmas “In the Kitchen” *
* Plasma 2010NRC, 2007
Plasma-processed microelectronics
Plasma ion-implanted artificial hip
Plasma TV
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Plasma Etching: IC Manufacture
Plasmas used to process semiconductors to make integrated circuits (ICs) –Nanoelectronics has replaced microelectronics: sub-10 nm critical dimensions
Advanced devices
Courtesy Y. Zhang, IBM Research
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Plasma biomedicine/sources/chemi
stry
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2010 G. Isbary: clinical trial for wound healing (MW Ar plasma)
2007 G. Fridman: in vitro cancer cell treatment (Air DBD)
Abbreviated History of Gas Plasmas In Biomedicine
1893 A. d’Arsonval: compatibility of HF with nerve and muscle
1926 Bovie knife: the first clinical use of a electrosurgical device
1940 Hyfrecator (Birtcher Co): low power and no ground pad
1995 APC (ERBE GmbH): Ar plasma for endoscopic surgery1993 Coblation (Arthrocare Co): discharge in saline solution
1999 M. Laroussi: E. coli sterilization (He DBD)
2003 E. Stoffels: non-destructive cell handling (He plasma needle)
2011 M. Vandamme/M. Keidar: in vivo cancer tumor treatment (jet/DBD)
2000 Plasma Surgical Company: Ar jet
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Atmospheric Pressure Plasma Sources for Biomedical Applications
(1) Drexel University (USA)(2) Cinogy GmbH (GER)(3) Old Dominion University (USA)(4) IOM Leipzig (GER)(5) Eindhoven Univ. of Techn. (NED)(6) New York University (USA)(7) MPE Garching (GER)(8) University of Orléans (FRA)(9) McGill University, Montreal (CAN)(10) Loughborough University (UK)(11) INP Greifswald (GER)
(1) (2)
(3) (4)
(6) (7)(5)(8)
(3)(9)
(6)
(10) (11)Courtesy:K.D. Weltmann,Greifswald
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Plasma Sources in Biomedicine: Microwave Ar plasma torch
J. Heinlin, JDDG 8 (2010) 968; G. Isbary, Br. J. Dermatol. 163 (2010) 78, Arch. Derm., 147 (2011), 388.
- Wound sterilization- Hailey-Hailey disease treatment
Prof.-Dr. G. MorfillMPE, Garching, Germany
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(2012)
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Before treatment After 7 days/ 5 sessions plasma treatment
*Richard M. Satava, MD FACSProfessor of SurgeryUniversity of Washington
Treatment of Topical Wounds: Tissue Regeneration: Suppurated Burn Wound (2009 conference)*
Plasma-induced wound healing: various anecdotal reports
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ground electrode
HV electrode(~5kV, 10kHz)
dielectricHV
Treated surface/fluid
Treated surface and ‘ground’
(a)Plasma Sources in Biomedicine:
Indirect and Direct DBD
(M. Vandamme, Plasma Process. Polym. 7 (2010) 264)
Prof. J.-M. Pouvesle,Univ. d’Orléans, France
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sample metal plate
HV HV
glasstube
metaltube
~ 1 cm
Rare Gas Jet Discharge (He or Ar)
Note: scalable via parallel jet arrays
M. Kong, LoughboroughUniv., UK
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Keidar et al., Dec. 2011; melanoma murine model
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…and in vitro (melanoma cells)
FE-DBD plasma in air
Sensenig et al., Oct. 29, 2010Annals Biomed. Eng.
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Plasmas in ambient air at room temperature
e
ion radical
hvE
• voltage: 10-20 kVpkpk• frequency: 1-10 kHz• power: ~ 1W• distance to finger: 1-3 mm• gas: static air in California
What are the Key Biochemical Agents??What are the Biochemical Mechanisms??
Cu
HV
glass
Object
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Plasma Needle: Can We Understand It?
• Frequency: RF (13.56MHz)• Voltage: 200-400 Vpkpk
• He flow rate: ~1 slpm (Red < 100)• Power consumption: ~1 W • Distance to sample: 1-5 mm
E. Stoffels, et al., Plasma Sources Sci. Tehcnol. 11 (2002) 383.
Function generator
RF amplifier He flow
Matching box
Air
glass tube(4 mm)
needle(0.5 mm)
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1 2 3 4 5 6 7
radial position
1.0 m/s
J.Goree, et al, J.Phys.D. 39 3479 (2006) and IEEE Trans.Plasma Sci. 34, 1317 (2006)
light intensity
1 2 3 4 5 6 7 8
radial position
0.3 m/s
5 mm
Plasma needle: Bactericidal effects
S. mutans• bacteria• anaerobic• oral cavity
alive
inactivated
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0
sgn( )
5 53 3
ii i
i i i i i i i
ee e e e
i i
n St
q n D n nn
n D Qt
q n
Γ
Γ E u
Γ Γ E
E
Plasma dynamics
(mass conservation)
(drift-diffusion)
(electron energy)
(Poisson’s equation)
electron, He*, He2
*, He+, He2
+,N2+
Neutral Gas flow (He, N2)
air air
p
0, 0
i i i
i i el
D
u p q n
T c T q Q
u u
u τ E
u Γ E
Fluid Model: Governing Equations
(mass conservation)
(momentum conservation)
(energy conservation)
He (~ 1m/s)
air (N2)
Y. Sakyiama et al, J. Appl. Phys. 101 (2007) 073306 and J. Phys. D 41 (2008) 95204
temperaturevelocity
species density ion momentum
collisional heating
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Chemistry Model: On-Axis and Off-Axis
Mole fraction of air (log scale)
on-axis off-axis
Killing pattern
inactivatedalive
10-6
10-4
10-2
mol
e fr
actio
n
2.01.51.00.50.0
10-6
10-4
10-2
mol
e fr
actio
n
1.00.50.0
on-axis
off-axis
1D plasma model
r [mm]
r [mm]
Air
Air
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Chemistry Model
46 species negative particles: e, O−, O2−, O3
−, O4−, H−, OH−
positive particles: He+, He2+, N+, N2
+, N3+, N4
+, O+, O2+, O4
+, NO+, N2O+, NO2
+, H+, OH+, H2O+, H3O+
neutrals: He, He*, He2*, N, N*, N2, N2*, N2**, O,O*, O2, O2*, O3, NO, N2O, NO2, NO3, H, H2, OH, H2O, HO2, H2O2
214 elementary reactions
• 21 electron impact excitation/ionization/dissociation reactions• 20 Penning and associative ionization reactions• 26 electron recombination/attachment reactions• 65 charge transfer reactions• 51 ion recombination reactions• 31 neutral-neutral reactions
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12
10
8
6
4
2
0
flux
[10
19 m
-2s-1
]
eN2
+
O2+He2
+
12
10
8
6
4
2
0
flux
[10
19 m
-2s-1
]
eN
O2+
H2O+ N2
+
O
O2*NOH OH
Species Fluxes to Surface
on-axis
off-axisReactiveneutrals
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Model Validation: O Atom Measurement *
• TALIF: two photon absorbed laser induced fluorescence• collaboration with Ruhr-Universitat Bochum (Germany)
N. Knake, et al, J. Phys. D: Appl. Phys. 41 (2008) 194006
* Thanks to:
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0.5 slpm 1.0 slpm
0.4 slpm 1.5 slpm
Measured O Atom Density: Qualitative Agreement with Model
Y. Sakiyama, et al., Appl. Phys. Lett. 97 (2010) 151501.
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SMD = surface micro-discharge(G. Morfill et al., New J. Phys. 11 (2009)
115019)Cross sectional view
HV
Frequency 1-10 kHzVoltage 1-10 kVpp
Power 0.01-1 W/cm2
Distance to sample 1-10 mmExposure time 1-1000 s
Atmospheric Pressure Air: SMD Device Configuration
Anti-microbial effect
• ~107 cfu/ml• 4-5 log-reduction in 30 s
Cu plate dielectric
SS mesh ~ 10 cm
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Model Predictions and Measurements
1017
1019
1021
1023
dens
ity
[m-3
]
10-2 100 102 104
density [ppm]
H2 H2O2
N2O
NO2
O3
N2O5
HNO2NO3
HNO3After 100 [s]
0.12
0.10
0.08
0.06
0.04
0.02
0.00
trans
mitt
ance
[-
]
4000 3000 2000 1000wave number [cm-1]
O3
HNO3
HNO3
N2O5HNO3 N2O5
N2O
FTIR measurement (qualitative comparison)
IR beam
200 scans for 60-120 [s]
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Reactive Oxygen and Reactive Nitrogen Species (RONS)
Reactive oxygen and nitrogen species often cited askey species in plasma biomedical applications.
But what is known about these species in biology and medicine?
One major focus of the talk is on these species andtheir role in biology and medicine
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Early Studies of RONS in Biomedicine
Chem. Reviews, 1938
Nature, 1954
Science, 1954
Science, 1956
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RONS in normal physiology and disease
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Overview of some cellularreactions/rolesof RONS
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Subset of RONS
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The field of antioxidants and free radicals is often perceived as focusing around the use of antioxidant supplements to prevent human disease. In fact, antioxidants/free radicals permeate the whole of life, creating the field of redox biology. Free radicals are not all bad, nor antioxidants all good. Life is a balance between the two: antioxidants serve to keep down the levels of free radicals, permitting them to perform useful biological functions without too much damage.
See also:
Related to the HUGE biomedical literature…, e.g.
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Reactive Oxygen Species: ROS
Radicals Nonradicals
ROS ROS
Halliwell, Plant Phys. 2006
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Radicals Nonradicals
Reactive chlorine Reactive chlorine
Reactive Chlorine/Bromine Species
Reactive bromine Reactive bromine
Halliwell, Plant Phys. 2006
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Radicals Nonradicals
Reactive nitrogen Reactive nitrogen
Reactive Nitrogen Species: RNS
Halliwell, Plant Phys. 2006
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Some Physiologic/Homeostatic Actions of RONS*
Oxidative Burst Immune Responses
Vascular Tone-Vasodilation-Blood pressure-Inhibit platelet aggregation
Neurotransmission-Pre/post synaptic transmitter-Long term potention/depression
Biomolecule Modification-Lipid/Protein function-Enzyme inhibition-Membrane stability
Cellular Response-Apoptosis-Metabolic turnover-Proliferation/differentiation
Signaling-MAP kinase-Redox-sensitive transcription factors
*Chiurchiu and Maccarrone, 2011Antioxidants and Redox Signaling
RONS
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Pacher et al., Physiol. Rev., 87, 315, 2007
In Vivo RONS Lifetimes/Diffusion Distances: Short!
~Radius of 50% peakconcentration from source
Enzymatic sources create species in certain places atcertain concentrations in response to certain events
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Reactive Species Play Major Role in Aerobic Biology:Example of Innate Immune System and Inflammation
SubsequentReactions
Many similar chemical species are created in air plasmas
Dedon and Tannenbaum, Archives of Biochemistry and Biophysics, 423, 2004
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Some Disease States Associated with RONS1. Cancer
2. Cardiovascular diseasea. Congestive heart failureb. Atherosclerosisc. Heart attackd. Stroke
3. Neurodegenerative diseasesa. Alzheimer’sb. Huntington’sc. Parkinson’sd. Multiple sclerosis
4. Inflammatory bowel disease
5. Diabetes
6. Rheumatoid arthritis
7. Lunga. Bronchial asthmab. Chronic obstructive pulmonary diseasec. Acute respiratory distress syndromed. Cystic fibrosis
8. Skina.Chronic skin inflammationb.Psoriasisc.Atopic dermatitisd.Acne
9. Eyesa.Macular degenerationb.Cataracts
10. Reproductive disordersa.Male/female infertilityb.preeclampsia c.hydatidiform mole d.fetal embryopathies
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When a Theory of Aging Ages Badly J. Lapointe and S. Hekimi
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“Because free radicals played such a major role in the evolutionof plants and animals they are an essential part of the basicbiology we study today…”
“The ability to sterilize a site of infection by rapid production ofROS can keep us alive. …it certainly did before antibiotics andantivirals entered clinical medicine.”
“During the 1980’s, antibiotics were shown to be redox activeand generate ROS. This led Gutteridge, Kovacic et al., in 1998 to propose that antibiotics mimic phagocytic cells by having acommon mechanism of microbial killing using ROS. This concepthas since been re-presented in detail [by Collins et al., 2007].”
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RONS in current therapeutics
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Collins et al. Cell, 2007
A Common Mechanism of Cellular Death from Bactericidal Antibiotics
A complex series of reactions creates OH via Fenton: all antibiotics allegedly functionthis way.
RONS as Therapy: Antibiotics
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Free Rad. Res., 1998
RONS as Therapy: Not So New!
“A wide variety of extracted and synthesized drug moleculeshave electron transfer capabilities which allow them to generateROS.”
“In particular, many antibiotics that kill or inhibit bacteria, yeastsand cancer cells readily transfer electrons to oxygen makingO2
- and H2O2…”
“This type of chemistry is very similar to that which evolvedwithin phagocytic cells as part of their microbial killing amoury.”
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Recall: DBD Air Plasma Cancer Cell Treatment
6 min X 5 days control
size of tumor
direct-mode air DBD
direct-mode air DBD (in vivo) (M. Vandamme, Plasma Process. Polym. 7 (2010) 264)
First in-vivo demonstration of anti-cancer actions of plasmas…
Leader: J.-M. Pouvesle, GREMI, Orléans, France
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Bio-Radicals Formed by Ionizing Radiation
O’Neil and Wardman
Formation of radicals thought to be central to cancer radiation therapy
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Castano et al., Nature Revs., 2006
Photodynamic Therapy Creates 1O2
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Pelicano et al., 2004
Cancer Chemotherapy and ROS Generationor Antioxidant Depletion/Inhibition
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Implications/questions for plasma medicine
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Reflections on Plasma-Generated Reactive SpeciesDynamics
• Many gas phase RONS will react quickly in biologicalfluid phase
• How can they have persistent bio-medical effects?
• Possibly by forming nitrated/oxidized lipids, proteins, etc.
• Example of nitrated fatty acids (NO2-FAs)
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Example: Air SMD-Water Chemistry*
H2O2
NO2-
NO3-
O3
*Pavlovich et al., accepted PPP, 2012
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Nitrated Fatty Acids NO2-FAs: Radical Reaction Pathways
Known products of airplasma in water: NyOxare known to react withPUFAs to form NO2-FAs
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Nitroalkene Biological/Therapeutic Activities
Nitratedlinoleic acid
Nitratedoleic acid
Nitratedarachidonic acid
Nitratedcholesteryllinoleate
OA-NO2
LNO2
AA-NO2
CLNO2
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Summary of RONS Importance in Biological Function
- RONS are known to play key roles in normal physiological functions such as cell signaling, vascular tone, neural transmission, apoptosis, etc.
- Well established that excessive RONS can be carcinogenic and are associated with many degenerative and other important diseases and aging
- RONS are also known to play key roles in immune system – mostly innate (inflammatory) system, but also adaptive system
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Summary of RONS Importance in Established Therapies
- The mechanisms of all antibiotics (e.g. Collins et al., 2007) and at least some antifungal and antiparasitic drugs (e.g. Artemisenin) appear to involve ROS generation.
- Many cancer therapies are based on the direct or indirect creation of RONS. Radiation therapy, photodynamic therapy (PDT) and certain chemotherapies all exploit this effect.
In other words, it is NOT SURPRISING that plasma medicine works - it is based on RONS chemistry that works in other therapies
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Confluence of Redox Biology and Plasma Science: Status
- But how do plasma-generated RONS work in detail?(e.g. through reactions with lipids/proteins?); Does plasma-generation of RONS provide unique advantages?
- Low temperature plasmas create RONS and other reactive species in relatively high densities at ambient gas temperature
- Preliminary positive results for infection control (disinfection/sterilization and antisepsis); wound healing; cancer therapy; various dermatology applications; dental wound/cavity/biofilm treatment; others
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More details: