Effect of Low Frequency Pulsed DC on Human Skin in Vivo.pdf

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Volume 104, Issue 5May 2009

www.sensorsportal.com ISSN 1726-547 9

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Sensors & Transducers Journal (ISSN 1726-5479) is a peer review international journal published monthly online by International Frequency Sensor Association (IFSA).Available in electronic and on CD. Copyright 2009 by International Frequency Sensor Association. All rights reserved.


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Volume 104Issue 5May 2009

www.sensorsportal.com ISSN 1726-5479

Research Articles

Biosensors Development Based on Potential Target of Conducti ng PolymersRavindra P. Singh and Jeong-Woo Choi............................................................................................ 1

Designing Binocul ar Stereo Omni-Directional Vision SensorsYi-ping Tang, Chen-jun Pang, Yi-hua Zhu ......................................................................................... 19

A Stainless Steel Electrode Phantom to Study the Forw ard Problem of Electr ical ImpedanceTomography (EIT)Tushar Kanti Bera and J. Nagaraju..................................................................................................... 33

Single-mode D-type Optical Fiber Sensor in Spectra Method at a Specific Incident Angleof 89Ming-Hung Chiu, Po-Chin Chiu, Yi-Hsien Liu, Wei-Ding Zheng ........................................................ 41

Effect of Low Frequency Pulsed DC on Human Skin in Vivo: Resistance Studies in ReverseIontophoresisPavan Kumar Kathuroju and Nagaraju Jampana............................................................................... 47

Low Frequency Noises of Hydrogen SensorsZara Mkhitaryan, Ferdinand Gasparyan, Armine Surmalyan............................................................. 58

Fe 2O3 - ZnO Based Gas SensorsL. A. Patil ............................................................................................................................................ 68

Effect of Yttria on Gas Sensitiv ity of Tungsten TrioxideM. H. Shahrokh Abadi, M. N. Hamidon, Rahman Wagiran, Abdul Halim Shaari, Norhisam Misron,Norhafizah Abdullah. .......................................................................................................................... 76

Liquefied Petroleum Gas (LPG) Sensing Propert ies of Nanosized Sprayed CdIn 2O4 Thin FilmsR. J. Deokate, R. R. Salunkhe, K. Y. Rajpure.................................................................................... 87

Optimization of a Novel Humidity Sensing Mechanism Strip LengthSouhil Kouda, Zohir Dibi, Abdelghani Dendouga, Samir Barra.......................................................... 96

Humidity Sensing Studies of WO 3-ZnO NanocompositeN. K. Pandey, Anupam Tripathi, Karunesh Tiwari.............................................................................. 109

Electrochemical Reduction of Potassium Ferricyanide Mediated by Magnesium DiborideModified Carbon ElectrodeWeeTee Tan, Farhan Yusri and Zulkarnain Zainal ............................................................................ 119

Authors are encouraged to submit article in MS Word (doc) and Acrobat (pdf) formats by e-mail: [email protected] visit journals webpage with preparation instructions: http://www.sensorsportal.com/HTML/DIGEST/Submition.htm

International Frequency Sensor Association (IFSA).


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Sensors & Transducers Journal, Vol. 104, Issue 5, May 2009, pp. 47-57

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Effect of Low Frequency Pulsed DC on Human Skin in Vivo:Resistance Studies in Reverse Iontophoresis

Pavan Kumar KATHUROJU and Nagaraju JAMPANADepartment of Instrumentation, Indian Institute of Science,

Bangalore, 560012, IndiaTel.: 91-80-22932273

E-mail: [email protected]

Received: 22 March 2009 /Accepted: 19 May 2009 /Published: 25 May 2009

Abstract: Instrumentation suitable for continuous monitoring of reverse iontophoresis in vivo inhuman subjects is developed. It supplies the required current and acquires the potential profile of theskin during reverse iontophoresis. Potential profiles showed that skin resistance decreases with theapplication of current. Experimental results revealed that the application of pulsed DC tends to makethe reverse iontophoresis more effective by enhancing the flow of analytes which is proved by the factthat resistance decreases and stabilizes faster in comparison to the one with direct current reverseiontophoresis. The paper emphasizes the importance of selecting an appropriate duty cycle and frequency for reverse iontophoresis. Duty cycle around 95 % and frequency of 250 mHz are good for low frequency reverse iontophoresis. Effect of reverse iontophoresis on the skin recovery is observed

by monitoring the potential profiles at the end of the process. In all the reverse iontophoresis

experiments, safety of the patient is ensured by fixing a compliance voltage level. Copyright 2009 IFSA.

Keywords: Pulsed DC, Reverse iontophoresis, Duty cycle, Skin resistance, Potential

1. Introduction

Skin has been seen as a possible route for administering drugs into the human body historically and also as a means of non-invasive sensing and diagnosis. Many attempts have been made in the past fewdecades to administer drugs across the stratum corneum of the skin into the systemic circulation.Advances in drug delivery systems owe to the growing research in the fields of iontophoresis,sonophoresis and associated methods for delivery and non invasive sensing.


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Iontophoresis is a process by which drugs are administered into the body by the application of electromotive force. During iontophoresis, for delivering a positively charged drug, it is dissolved inthe electrolyte surrounding the electrode of similar polarity. On application of an electromotive forcethe drug is repelled and moves across the stratum corneum towards the cathode, which is placed elsewhere on the body. Communication between the electrodes along the surface of the skin has been

shown to be negligible, i.e. movement of the drug ions between the electrodes occurs through the skinand not on the surface [1]. Similarly drugs/analytes could be extracted across the stratum corneum bythe reverse process called the Reverse Iontophoresis. As the movement of drugs is through the skin,skin behavior is of a very huge significance in non invasive sensing via the skin route. The studies oniontophoresis revealed that a few combination strategies could improve the iontophoretic drugdelivery. These include using Iontophoresis in combination with some of the other methods likeelectroporation, sonophoresis and in conjunction with chemical enhancers, micro needles, ionexchange materials. It reported that the skin irritation associated with iontophoresis has been addressed

by several studies and it is an issue preventing wide application of the technology [1].

High voltage pulses for small duration were also used for electrical creation of aqueous pathwaysacross the skin for skin electroporation [2]. Impedance of the skin reduces highly due to the applicationof high voltage pulses and recovery of skin after electroporation takes a very long time. As the time of application of the HV pulse was increases, recovery becomes difficult. Studies were useful to know theskin behavior and also in analyzing the blood flow with HV pulse applied [3]. It was also felt thatapplication of HV pulses increases the skin capacitances which gives the impression of changes in skinlipid structure [4], therefore skin recovery is a problem. Similarly, attempts on skin impedance studieswere made to see the effect of iontophoresis and permeation enhancers on female Yorkshire pigs [5]and was found that skin resistance is a measure of permeation of analytes. Similar studies were doneon human skin and skin impedance models were proposed [6-7]. It was also proposed that the skinresistance can be used not only as a compensation factor but also as a representing parameter for skinstatus, such as severe perspiration or stabilization phase. Invitro studies in the past revealed that theskin resistance change implies many phenomena during the reverse iontophoresis, particularly the skin

porosity. Therefore, it should be directly related to the amount of extracted solute [8].

Therefore, skin resistance is seen in recent times as an important factor which could be used inmonitoring the drug delivery as well as in non invasive sensing of analytes. The higher rate of decreasein skin resistance implies the higher rate of extraction and stabilization during reverse iontophoreticextraction. Therefore, instrumentation suitable for monitoring reverse iontophoresis and skin resistance

behavior is developed.

2. ExperimentationFig. 1 shows the schematic of the instrument developed for Reverse Iontophoretic monitoring. AnAC-DC current source (Keithley 6221) is used for application of direct and pulsed direct currents. Ithas features relating to very stable current delivery with a safety option provided in the form of compliance level settings. It is interfaced to the computer through GPIB (IEEE 488). A multimeter (Keithley 2002) is used to acquire the potential (resistance) information during the course of reverseiontophoresis experiments. More finer details of instrumentation are documented in M.Sc (Engg)thesis [9].

Ag/AgCl based gel electrodes are used for current delivery during reverse iontophoresis. These

electrodes are used as they are inert, work at low voltage, provide a stable environment for the analytesand minimize the transport of toxic species to the skin. The electrodes are placed on the forearm of thesubject at a distance 16mm apart. LabVIEW 7 is used for programming and controlling the


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instruments. Front end of the instrument developed for monitoring the reverse iontophoresis is shownin Fig. 2.

Fig. 1. Schematic of the instrumentation for monitoring Reverse Iontophoresis.

The front end consists of fields to input reverse iontophoretic parameters like current amplitude,frequency, duty cycle, number of samples. It also displays the potential profile, instantaneous potentialvalues along with the statistical data required for analysis. Provision exists on the front end to store thedata into the memory by creating an appropriate directory. Fig. 2 is a snapshot obtained while thereverse iontophoresis experiment was conducted on human in vivo for a current of 100 A with acompliance level of 20 V.

Fig. 2a. Front End of Reverse Iontophoresis Monitor. Pulsed DC Reverse Iontophoresis Potential profileis displayed on the waveform chart.


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Fig. 2b. Front End of the Reverse Iontophoresis Monitor. Waveform on the chart indicating the skin recovery profile after pulsed DC reverse Iontophoresis.

Constant current reverse iontophoresis experiments are conducted with a reverse iontophoretic currentof 20 A with a compliance level of 10 V. Potential difference between the electrodes is monitored throughout the reverse iontophoretic extraction process to get the idea of the resistance profile of theskin with current delivery. Effect of Reverse Iontophoresis on the skin is studied by monitoring the

potentials continuously after the reverse iontophoretic current delivery is stopped.

Later, similar experiments are conducted with pulsed DC. Pulsating direct current at very lowfrequencies (mHz) is applied to study the potential (resistance) profiles, time to obtain the steady

potential profile, there by indicating the steady flux of analytes with current delivery. The behavior of skin throughout and after the process is also monitored. Pulsed DC Iontophoresis experiments areconducted with pulsed direct current varying the duty cycle. Similar experiments are conducted at very

low frequencies of input pulsed current in the range 1 to 500 mHz. Very low frequency studies aretaken up to understand the resistance behavior of the skin (as skin capacitances dominate at the highfrequencies and in the case of HV Pulses for a very short duration).

3. Results and Discussion

Fig. 3 shows the potential profile of the skin acquired during constant direct current reverseiontophoresis with an input current of 20 A across the Ag/AgCl electrodes on the skin. Decrease inskin resistance is observed with time of application of current. This implies that there is an increase inthe extracted flux of analytes [8].


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0 1000 2000 3000 40005

6

7

8

9

10Reverse Iontophoresisconstant Direct current 20uA

P o t e n

t i a l ( V )

Time(s)

Fig. 3. Potential Profile of Constant Direct Current Reverse Iontophoresis.

This result is in accordance with the in vitro studies reported in the literature [5, 6, 8]. Potential profilestabilizes to a constant value only after the application of current for a very long duration. Reddeningof the skin under the electrodes is observed when current is applied for a long duration.

Fig. 4 shows the potential profile of the skin when pulsed DC is applied. It is observed that the potential falls with the application of pulsed DC. The rate of decrease in resistance is higher and thetime for stabilization of the potential is less than that for direct current reverse iontophoresis. The plotclearly shows the fall in potentials and the behavior of the skin closely with each pulse applied.Application of the pulsed current allows the skin to relax and thereby avoids the polarization of theskin towards a particular charge occurring due to continuous direct current.

Fig. 4. Pulsed DC Reverse Iontophoresis Potential Profile.


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Fig. 5a, 5b, 5c, 5d, 5e and 5f show the responses with pulsed DC applied with duty cycles of 70 %,75 %, 80 %, 85 %, 90 % and 95 % respectively. These studies revealed that by controlling the ON and OFF duration of the pulse, time for stabilization of reverse iontophoresis can be calculated and controlled. Pulse duty cycles around 95 % are found to be the best for pulsed DC ReverseIontophoresis at low frequencies.

(a) (b)

(c) (d)

(e) (f)

Fig. 5. Pulsed DC Reverse Iontophoresis at various Duty Cycles.


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Fig. 6 gives the stabilization time for various duty cycles. Fig. 6 shows that, as the duty cycle isincreased to 95 %, the rate of stabilization increased and the settling time for the process decreased.Potential profiles for the low frequency reverse iontophoresis are shown in Fig. 7. The effect of verylow frequency pulsed DC (mHz range) on reverse iontophoresis is shown in Fig. 8. It is observed thatfrequency of 250 mHz is good for low frequency reverse iontophoresis. The skin recovery after the

application pulsed DC reverse iontophoresis are shown in Fig. 9 and Fig. 10 for various duty cyclesand the low frequencies.

The skin recovery profiles follow an exponential decay pattern as shown. These potential decay profiles are just due to the skin getting back to normalcy after being charged because of application of pulsed DC. During the course of experiments it was also observed that the recovery takes longer timeas the magnitude of pulsed current is increased. Fig. 11 shows the recovery patterns of the skin after the reverse iontophoresis experiments with input currents of 100 A and 125 A. It has also beenfound that the problems like irritation and reddening of the skin caused by the application of constantDC current iontophoresis for long duration during continuous monitoring are solved by the pulsed DCapplication as the skin gains time for recovery with the OFF time in the pulse application.

Experimental results revealed that the application of pulsed DC tends to make the reverseiontophoresis more effective by enhancing the flow of analytes which is proved by the fact thatresistance values (voltage across the electrodes divided by the applied current) decreases rather quicklywith a higher slope to start with and finally reaching a steady value quickly in comparison to the onewith constant current reverse iontophoresis.

70 75 80 85 90 95 100

500

600

700

800

900

1000

1100

1200

1300

R e v e r s e

I o n

t o p h o r e s i s

t i m e

( s )

Duty Cycle %

Fig. 6. Effect of Duty cycle of the pulse on Reverse Iontophoresis.

For the studies conducted in vivo in human subjects, it was found in general that the fall in potentialclosely follows a third order polynomial varying with time before finally settling to a near constantvalue. The polynomial is of the form a+bx+cx 2+dx 3 with values of a, b, c, d ranging from 8 to 9.5, 0to -0.003, 6 E -7to 8E -7, - 5.5E -11 to -8E -11 (E stands for power of 10) respectively for pulsed DC reverse

iontophoresis, where x = t/2, t denotes the reverse iontophoresis time.


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(a) (b)

(c) (d)

(e) (f)

Fig. 7. Pulsed DC Reverse Iontophoresis at low frequencies.


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0 100 200 300 400 5001000

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i s t i m e ( s )

Frequency(mHz)

Fig. 8. Effect of low frequency pulsed DC on reverse iontophoresis.

0 250 500 750 1000-0.010

-0.005

0.000

0.005

0.010

0.015

0.020

0.025

0.030

0.035

p o t e n t i a l ( V )

Time(s)

100mHz200mHz300mHz400mHz500mHz

Frequency

Fig. 9. Skin Recovery Profiles after Low frequency Pulsed DC Reverse Iontophoresis.

0 200 400 600 800 1000-0.04

-0.03

-0.02

-0.01

0.00

0.01

0.02

0.03

0.04

P o t e n t i a l ( V )

Time(s)

959085807570

%Duty cycle

Fig. 10. Skin Recovery Profiles after Pulsed DC Reverse Iontophoresis for various duty cycles.


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Fig. 11. Skin recovery profiles for applied reverse iontophoretic current of 100 A and125 A.

4. Conclusions

It is observed that Pulsed DC reverse iontophoresis is better than direct current reverse iontophoresisfor in vivo applications. Skin resistance decrease and the potential profile stabilization is faster for

pulsed DC reverse iontophoresis. Pulse duty cycles around 95 % are good for Pulsed DC reverseiontophoresis. Frequency of around 250 mHz is good for low frequency reverse iontophoresis.Recovery of the skin after reverse iontophoresis is also monitored with the present setup. Recoverydepends on the magnitude of the applied reverse iontophoretic current. Pulsed DC can be applied for extraction of various analytes for diagnostic applications and can be used to study the effects of reverseiontophoretic extraction on the skin health. Further improvement of the system with inbuilt capabilitiesto monitor the skin impedance status by multi frequency impedance spectroscopy will lead to the self calibrated reverse iontophoresis systems for measurements and continuous monitoring.

References

[1]. Yiping Wang, Rashmi Thakur, Qiuxi Fan, Bozena Michniak, Transdermal iontophoresis: combinationstrategies to improve transdermal iontophoretic drug delivery, European Journal of Pharmaceutics and

Biopharmaceutics , 60, 2005, pp. 179-191.[2]. Nathalie Dujardin, Edith Staes, Yogeshvar Kalia, Peter Clarys, Richard Guy, Veronique Preat, In vivo

assessment of skin electroporation using square wave pulses, Journal of Controlled Release, 79, 2002, pp. 219-227.

[3]. Knut G. Hernes, Lars Morkrid, Asbjorn Fremming, Stein Odegarden, Orjan G. Martinsen, Hanne Storm,Skin conductance changes during the first year of life in full-term infants, Pediatric Research , Vol. 52,

No. 6, 2002.[4]. S. E. Cross, M. S. Roberts, Physical Enhancement of Transdermal Drug Application: Is Delivery

Technology Keeping up with Pharmaceutical Development ?, Current Drug Delivery , 1, 2004, pp. 81-92.[5]. Pankaj Karande, Amit Jain, Samir Mitragotri, Relationships between skins electrical impedance and

permeability in the Presence of chemical enhancers, Journal of Controlled Release, 110, 2006,

pp. 307 313.[6]. Yogeshvar N. Kalia, Richard H. Guy, Interaction between penetration enhancers and iontophoresis: effecton human skin impedance in vivo, Journal of Controlled Release, 44, 1997, pp. 33-42.


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[7]. Catherine Curdy, Yogeshvar N. Kalia, Franoise Falson-Rieg and Richard H. Guy, Recovery of HumanSkin Impedance In Vivo After Iontophoresis: Effect of Metal Ions, AAPS Pharmsci, 2000, 2, 3, article 23.

[8]. D. W. Kim, H. S. Kim, D. H. Lee, and H. C. Kim Importance of Skin Resistance in the ReverseIontophoresis-based Non-invasive Glucose Monitoring System, in Proceedings of the 26 th Annual

International Conference of the IEEE EMBS , San Francisco, CA, USA, September 1-5, 2004.[9]. K. Pavan Kumar, Instrumentation for Reverse Iontophoresis and Biosensor Capacitance Measurement,

Master of Science (Engineering) Thesis , Department of Instrumentation, Faculty of Engineering, IndianInstitute of Science, Bangalore, India, January 2008.

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