Problem Experimental Setup Conclusions The catheter is designed to be inserted into small animal blood vessels and human coronary arteries. Size: Max diameter no larger than 4 mm Length 5-10 cm Flexibility: Must bend at least 30º Range of motion not so great as to impede the flow of He Safety: Biocompatible catheter tube Ambient temperature plasma discharge Operation at atmospheric pressure Minimal He flow Fixed barrier to prevent He escape from tip of catheter into blood stream Target Plasma Operating Characteristics: (based on previous gas plasma needle designs) Forward power range from 100-300 mW Peak to peak voltages at electrode from 250-500 V He flow near 100 cc/min The RF function generator creates a plasma discharge at 13.56 MHz. The power meter reads the reflected and forward power through the transmission lines. The matchbox matches the impedances of the transmission line and plasma needle to minimize the reflected power. He flow is regulated by a flow meter from a compressed gas tank. Design a Working Gas Plasma Catheter: Design and build functioning plasma needle prototype Assemble experimental setup required for plasma generation Characterize functioning plasma needle Design a functioning catheter prototype for plasma delivery Fig. 5 Counter-Clockwise from Top: a) The gas-plasma discharge from the preliminary prototype onto the tip of a finger. The tissue acts as a ground and facilitates discharge. b) Preliminary prototype, using an extended glass tube to simulate the catheter attachment. c) The final design with catheter attached, utilizing an exhaust channel to allow helium circulation in a closed tip configuration. Fig. 4: Preventing plaque formation. The plasma discharge of the plasma needle creates free radicals that destroy the CAMs on the surface of the endothelium. With no ability to bind to the endothelium the molecule flows past the site treated with the gas-plasma needle. Transmigration does not occur, and thus plaque accumulation and the accompanying Dr. Eva Stoffels and her team of researchers at the Eindhoven University of Technology in the Netherlands have developed a novel gas plasma source, the “plasma needle”, which operates at room temperature, atmospheric pressure, and low power input. Specifically, this plasma is termed a low temperature non-equilibrium capacitive coupled radio frequent (RF) discharge. The discharge is achieved through application of a 13.56 MHz RF signal to He gas, resulting in partial ionization of the He gas, containing free electrons, positive/negative ions, radicals and various excited atoms and molecules. The plasma size is restricted through the use of a .3 mm diameter electrode and is visible as a spherical glow of about 1mm in diameter. The power density in this plasma is of the same order as in larger discharges, but the total consumed power is low (mW) due to the small volume. Similarly, the discharge remains cold because gas heating in plasmas is a volume effect. Fig. 2: Relationship between distance of electrode to surface being treated and number of free radicals. The number of species that interact with the surface increases by 10% for every 0.1 mm decrease in gap width within the 2 mm range 2 . Biomedical Application: The unique properties of the plasma needle permit its use for biomedical applications, previously unavailable to plasma due to temperature or pressure considerations. It has been demonstrated through in vitro testing that plasma needle treatment of cultured cells at power levels below 200mW universally results in cell detachment (see Fig. 1) 1. both from other cells and surfaces, without widespread necrosis or long term cell damage. This result has been isolated from the effect of UV radiation and the RF electrical field, and it is tentatively concluded that it is a result of destruction (e.g. oxidation) of Cell Adhesion Molecules (CAMs) by the reactive species emitted from the plasma. Further, the plasma needle has been found to stop proliferation of cells in culture without producing necrosis in as yet unpublished research by Dr. Stoffels and her colleagues. The power level, treatment time, and distance from the electrode to the surface (see Fig. 2) have been identified as the important factors in controlling dosage and resultant effects 2 . Fig. 1: Plasma-induced void 100 µm size on sheet of cultured cells. Cells treated with plasma needle at power < 50 mW. Cells were alive after plasma treatment 1 . Plasma Needle Technology Overview In order to maintain the plasma discharge in our experimental setup, a minimum forward power of 2.2 W was required, a considerably larger value than the target of 100 mW. At this forward power, the reverse power was only limited to 750 mW, corresponding to a reflected:forward ratio of 0.025. Optimally, a ratio approaching 5 x 10 -4 would be desired. The inability to achieve such desired precision in impedance matching was a result of the limitations in the auto-QRP tuner (the matching network). A custom tuned matching network could produce such results, as documented by members of Dr. Stoffel’s research team 7 , however construction of such could not be implemented in our project due to time limitations. The inefficient power transfer corresponded to a voltage amplitude range of nearly one order of magnitude lower than the target, 250-500 V. The plasma only ignited when there was a relative ground (i.e. grounded lead, finger or any living tissue) within 5 mm of the electrode tip. With a total blood vessel inner diameter of only 4 mm, the plasma would easily be close enough to the relative ground of the tissue to ignite. Time constraints did not allow for quantitative characterization of the plasma catheter. However, a gas plasma discharge was produced in the catheter configuration with qualitative requirements of the catheter met, albeit with a higher power input than that of the fixed preliminary prototype. The requirement for higher powers is likely due to the change in impedance characteristics resulting from a longer electrode. Fig. 3: How plaque forms from cholesterol and other molecules. Cholesterol inside the arterial lumen contacts the endothelium lining of the blood vessel wall and rolls along the endothelium tissue. CAMs attach to the molecule and then transmigrate the molecule through the endothelium into the intima, where it is deposited. The material accumulates to form plaque. Hypothesized Treatment Design Objectives Design Considerations * Connector length minimized to shortest length possible for effective coupling. 10 cm Electrode coating Silastic Silicone Hypodermic Needle 35 mm 35 mm 4.3 mm 2 m m PVC Connector Tube Shaft Length: 5 cm Outer Diameter: 4 mm Inner Diameter: 2.03 mm Electrode Diameter: 0.3 mm He Teflon Coating for Needle Electrode's Teflon Coating Hypodermic Needle Glass Tungsten Electrode Teflon Tube for He Flow Silastic Silicone Hypodermic Needle Teflon Coating for Needle Glass Electrode's Teflon Coating Tungsten Electrode 50 mm 35 mm 2 mm 87 mm Hypodermic Needle Helium flow 4.3 mm He Flexible Catheter Length: 10 cm Outer Diameter: 3.2 mm Inner Diameter: 2.0 mm Electrode Diameter: 0.3 mm Min* Fixed Preliminary Prototype Flexible Plasma Catheter General Assistance: Eva Stoffels, PhD Paul King, PhD Mary Jean Morris Lewis Saettel Franz Baudenbacher, PhD Electrical Engineering Assistance: Joel Barnett, PhD George Cook, PhD Robin Midgett A. B. Bonds, PhD Catheter Design Assistance: Raul Guzman, MD Frank Fish, MD Prince Kannankeril, MD Acknowledgements Materials Assistance: William Hofmeister, PhD (not drawn to scale) (not drawn to scale) Results Electrode Flexible Plasma Catheter Qualitative Characterization: Catheter meets size restrictions (see dimensions in Fig. 5 c). Silastic Silicone outer tubing provides for a flexible and biocompatible catheter. Plasma discharge present over full range of motion with bends in excess of 45º (see Fig. 9) Discharge maintains with thin plastic barrier in place sealing the end of the catheter from releasing He (see Fig. 8 Right) Exhaust method for He successfully prevents a buildup of pressure at the tip under sealed conditions Fig. 9: Functioning flexible plasma catheter bent at approximately 45º angle . Fig. 8 Left: Operating plasma catheter design. Right: Plasma glow can be seen through thin layer of plastic sealed over the tip of the catheter to prevent He flow out of the catheter. The metal held close to the needle is the grounded electrode. Non-thermal plasma was successfully produced between the electrode and ground (lead or finger) in both the fixed preliminary prototype and the flexible catheter prototype. Fixed Preliminary Prototype Quantitative Characterization: Size of plasma sphere roughly depends on the applied power: 0.4 mm to 1 mm diameter. Minimum He flow rate to maintain plasma: 167 cc/min. Maximum distance between electrode and ground to ignite plasma: 5 mm. Minimum forward power to maintain plasma: 2.2 W. Fig. 7 Left: Forward power input required to ignite and sustain (cutoff) plasma as the distance from the electrode to the grounding surface increased. (Flow maintained at a constant 187cc/min.) Right: Relationship between voltage at electrode and forward power. Fig. 6: Fixed preliminary prototype operating at a distance of approximately 4 mm. Fixed Preliminary Prototype Flexible Plasma Catheter Prototype Recommendations for Future Work Characterize the impedance of the plasma needle in the catheter design and construct a custom matching network to improve power transfer. Conduct in vitro experimentation on cultured cells in a simulated blood flow environment to investigate and characterize diffusion of the plasma active particles in the presence of bulk fluid transport. Identify and incorporate a suitable barrier at the catheter tip capable of preventing He escape but allowing passage of the active particles of plasma discharge. According to the National Heart, Lung and Blood Institute and the NIH, Coronary Artery Disease (CAD) is the number one killer of men and women in the United States, with 500,000 annual deaths attributed to heart attacks caused by CAD 3,4 . CAD is caused by atherosclerosis in the coronary arteries when plaque buildup restricts the oxygen and nutrient flow to the heart and leads to angina, heart attack, or sudden death. Current treatments for CAD include balloon angioplasty, stents or coronary artery bypass surgery, yet none seek to prevent plaque accumulation. Specific Problem: Plaque accumulates in the arterial blood vessels due to the interaction between Cell Adhesion Molecules (CAMs) and molecules of cholesterol, fat, and other materials found in the blood 5 . Molecules contact the endothelium wall of the lumen and roll alongside the wall, making contact with the molecules on the endothelium. Molecules bind to CAMs and stick to the endothelium wall 6 . Transmigration of the molecules through the endothelium and into the intima of the arterial vessel deposits the molecule where it can accumulate over time to form plaque. Destroying CAMs prevents molecules from sticking to the endothelium and therefore no accumulation of plaque occurs. Applying this technique to an area in danger of plaque growth could curtail further growth, preventing narrowing of the artery and, by extension, angina and heart attack. A catheter capable of delivering plasma discharge – and the accompanying discharge of free radicals – can be used in vivo in arteries to prevent plaque growth. 0 2 4 6 8 10 12 0 1 2 3 4 5 D istance (m m) Forward Power(W ) cutoff ignition 0 5 10 15 20 25 0 200 400 600 800 1000 1200 Forw ard P ow er(m W) Am plitude (V p-p)
ProblemExperimental SetupConclusions The catheter is designed to be inserted into small animal blood vessels and human coronary arteries. Size: Max diameter.
Jan 20, 2016
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Problem
Experimental Setup
Conclusions
The catheter is designed to be inserted into small animal blood vessels and human coronary arteries.
Size: Max diameter no larger than 4 mm Length 5-10 cmFlexibility: Must bend at least 30º Range of motion not so great as to impede the flow of He Safety: Biocompatible catheter tube Ambient temperature plasma discharge Operation at atmospheric pressure Minimal He flow Fixed barrier to prevent He escape from tip of catheter into blood stream Target Plasma Operating Characteristics: (based on previous gas plasma needle designs) Forward power range from 100-300 mW Peak to peak voltages at electrode from 250-500 V He flow near 100 cc/min
The RF function generator creates a plasma discharge at 13.56 MHz. The power meter reads the reflected and forward power through the transmission lines. The matchbox matches the impedances of the
transmission line and plasma needle to minimize the reflected power. He flow is regulated by a flow meter from a compressed gas tank.
Design a Working Gas Plasma Catheter: Design and build functioning plasma needle prototype Assemble experimental setup required for plasma generation Characterize functioning plasma needle Design a functioning catheter prototype for plasma delivery
Fig. 5 Counter-Clockwise from Top: a) The gas-plasma discharge from the preliminary prototype onto the tip of a finger. The tissue acts as a ground and facilitates discharge. b) Preliminary prototype, using an extended glass tube to simulate the catheter attachment. c) The final design with catheter attached, utilizing an exhaust channel to allow helium circulation in a closed tip configuration.
Fig. 4: Preventing plaque formation. The plasma discharge of the plasma needle creates free radicals that destroy the CAMs on the surface of the endothelium. With no ability to bind to the endothelium the molecule flows past the site treated with the gas-plasma needle. Transmigration does not occur, and thus plaque accumulation and the accompanying narrowing of the artery never occurs.
Dr. Eva Stoffels and her team of researchers at the Eindhoven University of Technology in the Netherlands have developed a novel gas plasma source, the “plasma needle”, which operates at room temperature, atmospheric pressure, and low power input. Specifically, this plasma is termed a low temperature non-equilibrium capacitive coupled radio frequent (RF) discharge. The discharge is achieved through application of a 13.56 MHz RF signal to He gas, resulting in partial ionization of the He gas, containing free electrons, positive/negative ions, radicals and various excited atoms and molecules. The plasma size is restricted through the use of a .3 mm diameter electrode and is visible as a spherical glow of about 1mm in diameter. The power density in this plasma is of the same order as in larger discharges, but the total consumed power is low (mW) due to the small volume. Similarly, the discharge remains cold because gas heating in plasmas is a volume effect.
Fig. 2: Relationship between distance of electrode to surface being treated and number of free radicals. The number of species that interact with the surface increases by 10% for every 0.1 mm decrease in gap width within the 2 mm range2.
Biomedical Application:
The unique properties of the plasma needle permit its use for biomedical applications, previously unavailable to plasma due to temperature or pressure considerations. It has been demonstrated through in vitro testing that plasma needle treatment of cultured cells at power levels below 200mW universally results in cell detachment (see Fig. 1)1. both from other cells and surfaces, without widespread necrosis or long term cell damage. This result has been isolated from the effect of UV radiation and the RF electrical field, and it is tentatively concluded that it is a result of destruction (e.g. oxidation) of Cell Adhesion Molecules (CAMs) by the reactive species emitted from the plasma. Further, the plasma needle has been found to stop proliferation of cells in culture without producing necrosis in as yet unpublished research by Dr. Stoffels and her colleagues. The power level, treatment time, and distance from the electrode to the surface (see Fig. 2) have been identified as the important factors in controlling dosage and resultant effects2.
Fig. 1: Plasma-induced void 100 µm size on sheet of cultured cells. Cells treated with plasma needle at power < 50 mW. Cells were alive after plasma treatment1.
Plasma Needle Technology Overview
In order to maintain the plasma discharge in our experimental setup, a minimum forward power of 2.2 W was required, a considerably larger value than the target of 100 mW. At this forward power, the reverse power was only limited to 750 mW, corresponding to a reflected:forward ratio of 0.025. Optimally, a ratio approaching 5 x 10-4 would be desired. The inability to achieve such desired precision in impedance matching was a result of the limitations in the auto-QRP tuner (the matching network). A custom tuned matching network could produce such results, as documented by members of Dr. Stoffel’s research team7, however construction of such could not be implemented in our project due to time limitations. The inefficient power transfer corresponded to a voltage amplitude range of nearly one order of magnitude lower than the target, 250-500 V.
The plasma only ignited when there was a relative ground (i.e. grounded lead, finger or any living tissue) within 5 mm of the electrode tip. With a total blood vessel inner diameter of only 4 mm, the plasma would easily be close enough to the relative ground of the tissue to ignite.
Time constraints did not allow for quantitative characterization of the plasma catheter. However, a gas plasma discharge was produced in the catheter configuration with qualitative requirements of the catheter met, albeit with a higher power input than that of the fixed preliminary prototype. The requirement for higher powers is likely due to the change in impedance characteristics resulting from a longer electrode.
Fig. 3: How plaque forms from cholesterol and other molecules. Cholesterol inside the arterial lumen contacts the endothelium lining of the blood vessel wall and rolls along the endothelium tissue. CAMs attach to the molecule and then transmigrate the molecule through the endothelium into the intima, where it is deposited. The material accumulates to form plaque.
Hypothesized Treatment
Design Objectives
Design Considerations
* Connector length minimized to shortest length possible for effective coupling.
10 cm
Electrode coating
Silastic Silicone
HypodermicNeedle
35 mm35 mm
4.3 mm
2 mm
PVC Connector Tube
Shaft
Length: 5 cm
Outer Diameter: 4 mm
Inner Diameter: 2.03 mm
Electrode Diameter: 0.3 mm
He
Teflon Coating for Needle
Electrode's Teflon Coating
Hypodermic Needle
Glass
Tungsten Electrode
Teflon Tube for He Flow
Silastic Silicone
Hypodermic Needle
Teflon Coating for Needle
Glass
Electrode's Teflon Coating
Tungsten Electrode
50 mm35 mm
2 mm
87 mm
HypodermicNeedle
Helium flow
4.3 mm
He
Flexible Catheter
Length: 10 cm
Outer Diameter: 3.2 mm
Inner Diameter: 2.0 mm
Electrode Diameter: 0.3 mm
Min*
Fixed Preliminary Prototype Flexible Plasma Catheter
General Assistance:Eva Stoffels, PhDPaul King, PhDMary Jean MorrisLewis SaettelFranz Baudenbacher, PhD
Electrical Engineering Assistance:Joel Barnett, PhDGeorge Cook, PhDRobin MidgettA. B. Bonds, PhD
Catheter Design Assistance:Raul Guzman, MDFrank Fish, MDPrince Kannankeril, MD
Acknowledgements
Materials Assistance:William Hofmeister, PhD
(not drawn to scale) (not drawn to scale)
Results
Electrode
Flexible Plasma Catheter Qualitative Characterization: Catheter meets size restrictions (see dimensions in Fig. 5 c). Silastic Silicone outer tubing provides for a flexible and biocompatible catheter. Plasma discharge present over full range of motion with bends in excess of 45º (see Fig. 9) Discharge maintains with thin plastic barrier in place sealing the end of the catheter from releasing He (see Fig. 8 Right) Exhaust method for He successfully prevents a buildup of pressure at the tip under sealed conditions
Fig. 9: Functioning flexible plasma catheter bent at approximately 45º angle .
Fig. 8 Left: Operating plasma catheter design. Right: Plasma glow can be seen through thin layer of plastic sealed over the tip of the catheter to prevent He flow out of the catheter. The metal held close to the needle is the grounded electrode.
Non-thermal plasma was successfully produced between the electrode and ground (lead or finger) in both the fixed preliminary prototype and the flexible catheter prototype.
Fixed Preliminary Prototype Quantitative Characterization: Size of plasma sphere roughly depends on the applied power: 0.4 mm to 1 mm diameter. Minimum He flow rate to maintain plasma: 167 cc/min. Maximum distance between electrode and ground to ignite plasma: 5 mm. Minimum forward power to maintain plasma: 2.2 W.
Fig. 7 Left: Forward power input required to ignite and sustain (cutoff) plasma as the distance from the electrode to the grounding surface increased. (Flow maintained at a constant 187cc/min.) Right: Relationship between voltage at electrode and forward power.
Fig. 6: Fixed preliminary prototype operating at a distance of approximately 4 mm.
Fixed Preliminary Prototype
Flexible Plasma Catheter Prototype
Recommendations for Future Work Characterize the impedance of the plasma needle in the catheter design and construct a custom matching network to improve power transfer. Conduct in vitro experimentation on cultured cells in a simulated blood flow environment to investigate and characterize diffusion of the plasma active particles in the presence of bulk fluid transport. Identify and incorporate a suitable barrier at the catheter tip capable of preventing He escape but allowing passage of the active particles of plasma discharge.
According to the National Heart, Lung and Blood Institute and the NIH, Coronary Artery Disease (CAD) is the number one killer of men and women in the United States, with 500,000 annual deaths attributed to heart attacks caused by CAD3,4. CAD is caused by atherosclerosis in the coronary arteries when plaque buildup restricts the oxygen and nutrient flow to the heart and leads to angina, heart attack, or sudden death. Current treatments for CAD include balloon angioplasty, stents or coronary artery bypass surgery, yet none seek to prevent plaque accumulation.
Specific Problem: Plaque accumulates in the arterial blood vessels due to the interaction between Cell Adhesion Molecules (CAMs) and molecules of cholesterol, fat, and other materials found in the blood5. Molecules contact the endothelium wall of the lumen and roll alongside the wall, making contact with the molecules on the endothelium. Molecules bind to CAMs and stick to the endothelium wall6. Transmigration of the molecules through the endothelium and into the intima of the arterial vessel deposits the molecule where it can accumulate over time to form plaque.
Destroying CAMs prevents molecules from sticking to the endothelium and therefore no accumulation of plaque occurs. Applying this technique to an area in danger of plaque growth could curtail further growth, preventing narrowing of the artery and, by extension, angina and heart attack. A catheter capable of delivering plasma discharge – and the accompanying discharge of free radicals – can be used in vivo in arteries to prevent plaque growth.
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0 1 2 3 4 5
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Forw
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cutoff
ignition
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