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Substrate Electrode Morphology Affects Electrically Controlled Drug Release from Electrodeposited Polypyrrole Films Michael S. Freedman1, Xinyan Tracy Cui*2,3,4 School of Medicine, University of California‐San Francisco, San Francisco, CA 94117, USA
1
Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15260, USA 2
Center for Neural Basis of Cognition, Pittsburgh, PA 15260, USA
3
McGowan Institute for Regenerative Medicine, Pittsburgh, PA 15260, USA
4 *
xic11@pitt.edu
Received 28 January 2014; Accepted 27 February 2014; Published 17 October 2014 © 2014 BIOLOGICAL AND CHEMICAL PUBLISHING Abstract This study aims to understand how substrate electrode surface morphology affects the drug releasing capacity of the overlaying conducting polymer film. Fluorescein was used as a model drug to dope the conducting polymer polypyrrole (PPy). To examine the effects of electrode surface morphology, gold electrodes were electrodeposited for increasing periods of time with platinum, effectively increasing the surface roughness of the electrode. Equivalent circuit analysis and cyclic voltammetry further suggested the increase in surface area as Pt deposition time increased. Polypyrrole films doped with fluorescein were then electropolymerized on the platinized electrode surfaces. An increase in electrically stimulated fluorescein release from the electrode surface was observed with increasing substrate roughness. Subsequently, an increase in release per charge accumulation used during electropolymerization was also observed, indicating that releasable drug occupies a higher fraction of the polymer film deposited on rougher surface. Finally, the release per charge injected during electrical stimulation also increased as the substrate surface area increased, suggesting increased release efficiency from rougher electrode substrates. To our knowledge, this is the first time the relationship of increased drug release and release efficiency from rougher substrates has been experimentally verified. Keywords Conducting Polymer; Drug Delivery; Fluorescein; Platinum Black; Polypyrrole
Introduction Electroactive conducting polymers such as poly(3,4‐ethylenedioxythiophene) or PEDOT and polypyrrole (PPy) are of considerable interest in a variety of biomedical applications including neural prosthetics, drug delivery, tissue engineering and biosensors (Zinger and Miller 1984; Boyle, Genies et al. 1990; Pyo, Maeder et al. 1994; Kontturi, Pentti et al. 1998; Garner, Georgevich et al. 1999; Collier, Camp et al. 2000; Pernaut and Reynolds 2000; Cen, Neoh et al. 2004; Abidian, Kim et al. 2006; Ateh, Navsaria et al. 2006; Thompson, Moulton et al. 2006; Wadhwa, Lagenaur et al. 2006; Guimard, Gomez et al. 2007; Ravichandran, Sundarrajan et al. 2010; Turkarslan, Boyukbayram et al. 2010). They have been shown to have excellent biocompatibility and low electrical impedance (Collier, Camp et al. 2000; Cen, Neoh et al. 2004; Abidian, Kim et al. 2006; Ateh, Navsaria et al. 2006; Guimard, Gomez et al. 2007). Additionally, electrochemical polymerization of these conducting polymers is accompanied by the incorporation of anionic dopant molecules. Choice of dopant allows further adaptability of the polymer for various applications (Miller, Zinger et al. 1987; Boyle, Genies et al. 1990; Pyo, Maeder et al. 1994; Kontturi, Pentti et al. 1998; Collier, Camp et al. 2000; Pernaut and Reynolds 2000; Wadhwa, Lagenaur et al. 2006; Guimard, Gomez et al. 2007). Large, biologically active dopants often result in irreversible integration with the polymer film customized for
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specific applications. PPy films have been doped with bioactive molecules for increased biocompatibility, including heparin (Garner, Georgevich et al. 1999; Garner, Hodgson et al. 1999), hyaluronan (Collier, Camp et al. 2000), silk‐like polymer with fibronectin fragments, and peptide sequences of laminin (Cui, Lee et al. 2001; Stauffer and Cui 2006). Small dopant molecules, on the other hand, may be released from the polymer film according to the mechanism described below. Conducting polymers may undergo reversible redox reaction upon electrical stimulation (Boyle, Genies et al. 1990). As the polymer film is oxidized or reduced, the backbone becomes charged or neutral, and ions flow into or out of the polymer film to maintain charge balance. The ionic flux is accompanied by changes in volume of the polymer as it expands and contracts (Abidian, Kim et al. 2006). As a result of the discharge of the polymer backbone, the electrical association of the polymer to charged anionic doping molecules will be broken and dopants will be released. Consequently, controlled release of the dopant molecules can be achieved through electrical stimulation (Wadhwa, Lagenaur et al. 2006). A wide range of compounds with different clinical applications have been released from polypyrrole films in this fashion, including fluorescein (Luo and Cui 2009), Fe(CN)64‐ (Zinger and Miller 1984; Miller, Zinger et al. 1987), glutamate (Zinger and Miller 1984), 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX) (Stauffer 2009), salicylate, naproxen (Kontturi, Pentti et al. 1998), Adenosine‐5ʹ‐triphosphate (ATP) (Pyo, Maeder et al. 1994; Pernaut and Reynolds 2000), biotinylated NGF (George, LaVan et al. 2006), dexamethasone (Wadhwa, Lagenaur et al. 2006), and neurotrophin‐3 (NT‐3) (Thompson, Moulton et al. 2006). Conducting polymer‐based delivery holds great potential in the field of neural interface. They have been studied for use in cochlear implants, eluting brain‐derived neurotrophic factor (BDNF) and NT‐3 to preserve spiral ganglion neurons after hearing loss (Richardson, Thompson et al. 2007; Evans, Thompson et al. 2009; Richardson, Wise et al. 2009). Administration of dexamethasone has been shown to improve chronic performance of neural probes (Shain, Spataro et al. 2003), and incorporating dexamethasone into a conducting polymer film is a logical progression. Release of cationic drugs such as dimethyldopamine (Zhou, Miller et al. 1989) and chlorpromazine (Hepel and Mahdavi 1997) from conducting polymer films expands the potential use of this drug delivery systems to include neurophysiology research and clinical therapy by incorporating specific neurotransmitters and other neurological drugs. Based on this mechanism, neurotransmission inhibitors CNQX and AP‐5 delivery have been applied to neural electrode arrays and the release of these drugs at precisely defined temporal and spatial resolution is used to manipulate cultured neural networks (Stauffer 2009). While conducting polymer drug delivery has many promising aspects, several limitations of the technology exist including drug loading capacity, drug release efficiency and restriction on molecular size and charge of the drug molecules. Although increasing the volume of the polymer film will directly increase the amount of drug loaded in the film, drug residing in the inner layer of thicker films is difficult to release unless longer or stronger electric stimuli are applied, which could increase the risk of tissue damage (Wadhwa, Lagenaur et al. 2006). In addition, for many neural implant applications, increasing thickness means increasing the size of the implant, which will lead to more inflammatory host tissue response. We hypothesize that increasing the substrate roughness will add more surface area for polymer deposition, and increase quantity of drug release as well as release efficiency. Electroplating of platinum black (Pt‐black) is one method of varying the morphology of electrode surfaces. Pt‐black coated electrodes have shown to reduce impedance of microelectrode arrays, improving their performance for both neural recording and neural stimulation (Desai, Rolston et al. 2010). In this study, the surface morphology of the electrode surface was modulated by electrodeposition of platinum, which produced surfaces with varying roughness. Polypyrrole doped with model drug molecule fluorescein was electrodeposited on to various surfaces. Fluorescein was chosen because of the ease and sensitivity with which it can be detected. Fluorescein release was quantified for a range of platinized surfaces. To characterize the degree of release attributed to diffusion, fluorescein release due to an electrical stimulus was compared to that of an equivalent period of time in solution with no electrical stimulus. Materials and Methods Chemicals Pyrrole (98%, Sigma‐Aldrich) was vacuum distilled. Plastic microscope coverslips were purchased from Fisher.
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Waater was deiionized usin ng a Milli‐Q Q water purification systtem. Fluoresscein sodium m salt was purchased p frrom Sig gma‐Aldrich. All other reeagents are aanalytical graade. Eleectrochemica al System Eleectrochemicaal experimen nts were carriied out using g a Potentiosstat, FAS2/Feemtostat (Gaamry Instrum ments) in a 2 mL recctangular cuvette. In two o‐electrode setup, s electro ochemical ex xperiments were w carried d out againstt a 10 mm × × 20 mm m rectangulaar platinum electrode. In n three‐electrrode setup, electrochemi e istry was peerformed usin ng an Ag/Ag gCl refference electrrode and thee same platin num counter electrode. Eleectrode Preparation Co overslips werre cut to un niform dimen nsion of 7 × 22 mm2, cleeaned with 8N 8 HNO3 fo or 30 min, washed w twicee in deiionized H2O and once in O n ethanol. Th he clean coveerslips were tthen sputter coated with h a 40 nm thick layer of g gold usiing a Cressin ngton Sputter Coater. Thee gold‐coated d coverslips (electrodes) were stored in a desiccattor until use.. Eleectrodepositiion of Platin num Th he platinizatiion solution was prepared by stirrin ng 1.0 g chlo oroplatinic acid a and 10 mg lead aceetate in 100 mL deiionized H2O for 24 hour O rs. The electrrodes were ellectrodeposited with plaatinum black k (Pt‐black) a amperostaticaally usiing a two‐eleectrode setup p with 1 mL of platinizattion solution.. Current of ‐‐5.0 mA wass applied to tthe electrode for 25,, 50, 100, or 2200 seconds. The coversliips were then n gently wasshed under d deionized H2O O for 10 seco onds. Eleectropolymerrization of P PPy/Fluoresccein Films Th he electrodess of varying Pt‐black thicknesses weere immersed d in a 1.0 mL m solution o of 0.5 M pyrrrole and 0.11 M flu uorescein in D DI H2O. PPy//fluorescein films were eelectropolym merized poten ntiostatically y using a volttage of 0.7 V for 2000 seconds wiith a three‐ellectrode setu up. Drrug Release Th he electrochem mically conttrolled drug release was carried out with a two‐eelectrode settup. A 10 seccond pulse w was applied to thee PPy/fluoresscein coated d electrodes at a constant magnitud de of ‐2.0 V V in a volum me of 1.0mL L of ph hosphate bufffered saline (PBS). To discern d diffu usion‐mediatted drug rellease from eelectrochemiccally controllled dru ug release, PPy/fluoresc P cein prepared d electrodes were allow wed to sit in the cuvette for an equa al time with no stim mulus. The eelectrode preeparation and d drug releasse are illustra ated in Schem me 1. Th he resulting concentratio on of fluoreescein in so olution was quantified using a SpeectraMax M5 M plate reaader (M Molecular Deevices). The excitation and a emission n wavelengths for fluo orescein werre set at 405 5 and 538 nm, n resspectively.
SCH. 1 GENERAL LIZED EXPERIM MENTAL SETU UP SHOWING E ELECTRODEPO OSITION OF PLA ATINUM (A), E ELECTROPOLY YMERIZATION N OF POLYPY YRROLE (B), AN ND CONTROLL LED DRUG REL LEASE (C)
Surface Characcterization 1) Scannin ng Electron M Microscopy ((SEM) SEM was perfo ormed with aan XL30 SEM M instrumen nt (FEI Comp pany). The saamples were sputter‐coatted with a 3 nm thiick layer of gold g to ensu ure conductiv vity. Accelerration potenttial of 5 kV was used fo or imaging th he samples at a a
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range of magnifications. 2) Electrochemical Impedance Spectroscopy Electrochemical impedance spectroscopy (EIS) was performed on the electrodes coated with Pt‐black using a three‐electrode setup in 400 μL of PBS at 0 V bias vs Ag/AgCl at an amplitude of 5 mV rms. The surface area was decreased from 0.7 cm2 to 0.14 cm2 by using adhesive tape to leave only the bottom 2 mm of the electrode exposed and prevent capillary action of the solution up the electrode surface. This shifted the limits of the impedance spectrum to within practical bounds. Impedances were measured between 0.01 Hz and 1.0 kHz at 10 points per decade. Equivalent circuit models were evaluated using Gamry EChem Analyst software (Gamry Instruments). 3) Cyclic Voltammetry Cyclic voltammetry (CV) was performed in the same three‐electrode setup used in EIS measurement. Prior to running the CV, the solution was purged with N2 for 5 minutes, and nitrogen atmosphere was kept during the experiment. The potential was swept from ‐0.6 V to +0.5 V at a scan rate of 100 mV/s for three cycles. The current of the second cycle was integrated to calculate charge capacity of the electrode surfaces.
FIG. 1 SEM IMAGES OF ELECTRODE SURFACES. THE COLUMNS A, B, AND C ILLUSTRATE THE PLATINIZED ELECTRODE SURFACE, THE PPY/FLUORESCEIN FILM ON THE ELECTRODE SURFACE AFTER DIFFUSION, AND THE PPY/FLUORESCEIN FILM ON THE ELECTRODE SURFACE AFTER A 10 S ELECTRICAL STIMULUS OF ‐2.0 V, RESPECTIVELY. THE ROWS 1, 2, 3, 4, AND 5 SHOW ELECTRODE SURFACES OF 0, 25, 50, 100, AND 200 S PLATINIZATION DURATIONS
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Re esults Surface Characcterization Scaanning electrron micrograaphs revealed d increased ssurface roug ghness with iincreasing du uration of platinization. T The surrface of the 100 and 2000 s platinum m surfaces appeared a to have a more nodular m microstructurre, whereas the eleectrode surfaaces with sh horter durations of platin nization werre characteriized by a m more discrete morphological rou ughness (Fig g. 1). Once co oated with PP Py/fluoresceiin, the less ro ough electro ode surfaces d did not undeergo any visiible chaanges, whilee the rough edges obserrved on the thicker plattinum surfacces were rep placed by sm moother surfface feaatures. Eleectrochemica al Impedancee Spectroscop py Eq quivalent circcuit modelin ng was used to obtain a ssemi‐quantitative evaluation of the eeffective surfface area for the plaatinized surffaces. The model m used was w a resistorr in series with w a resisto or and constaant phase element (CPE)) in parallel (Fig. 2). This model m has previously p b been used to t describe the electrod de‐electrolytte interface on eleectrodepositeed gold electtrodes (Cui and a Martin 22003; Orazem m and Tribo ollet 2008). T The parameteer RS represeents thee resistance o of the solutio on. The CPE is a non‐intu uitive circuitt element and d its behavio or may rise ffrom a variattion of properties at the surfacee or along thee direction n normal to thee surface. In our system, the variabiliity is likely d due to the porosity y and surfacee roughness (Cui and Maartin 2003). M Mathematicaally, the impedance of CP PE is expressed as Z = 1/[Q0(jω)n]. Both Q0 aand n are paarameters ind dependent off frequency. When n=1, Q Q0 is simply the capacitance 2 n (F//cm ), and is proportionaal to the actiive surface aarea. When n n1, Q0 has aa unit of s / cm2 and thee system sho ows beh havior attrib buted to disp persion of tim me constantts (Orazem and a Tribollett 2008). The parameter Rp is defined d as chaarge transferr resistance aat electrode‐eelectrolyte in nterface, whicch is not a fu unction of thee electrode su urface area.
FIG. 2 EQUIV VALENT CIRCU UIT MODEL US SED TO CALCU ULATE EQUIVA ALENT CAPAC CITANCE OF TH HE ELECTROD DE SURFACES 10 9 8
-Z{Im} / kΩ
7 6 5 4 3 Experim mental 2 Fit 1 0 0
2
4
6
Z{Re} / kΩ Ω
F FIG. 3 NYQUIS ST PLOT OF TH HE IMPEDANCE E OF THE 200 S S PLATINUM ELECTRODE SU URFACE FITTED D WITH ITS EQU UIVALENT CIR RCUIT CURVE
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An example of the fit of the equivalent circuit model is shown in Fig. 3. Parameters of RS, RP, and n and Q0 from the CPE for each electrode surface were obtained. The solution resistance is similar for all surfaces, which is expected as the same solution was used. Values of capacitance were calculated using the equation C = ((Q0*RP)(1/n))/RP. A direct correlation was demonstrated between capacitance and duration of platinization (Table 1). Increasing platinization time led to higher capacitance, which is linearly related to the effective surface area of the electrodes (Orazem and Tribollet 2008). TABLE 1 CALCULATED PARAMETERS FROM THE EQUIVALENT CIRCUIT MODELING OF ELECTRODE SURFACE (N=4)
Platinum Deposition Time / s 25 50 100 200
RP / kΩ 239 ± 74 68 ± 28 100 ± 27 37 ± 17
RS / Ω 153 ± 11 143 ± 7 145 ± 11 142 ± 12
Q0 / μS*sn 104 ± 21 149 ± 33 274 ± 79 469 ± 160
n / no units 0.828 ± 0.006 0.829 ± 0.018 0.813 ± 0.014 0.799 ± 0.015
Equivalent C / μF 190 ± 95 224 ± 112 537 ± 269 852 ± 426
A
B
FIG. 4 (A) CYCLIC VOLTAMMOGRAMS OF EACH OF THE ELECTRODE SURFACES BETWEEN ‐0.6 V AND +0.5 V AT A SCAN RATE OF 100 MV/S. ARROW DIRECTION INDICATES INCREASING DURATION OF PLATINIZATION ON ELECTRODE SURFACES. (B) CHARGE CAPACITY OF ELECTRODE SURFACES OF VARYING PT‐BLACK THICKNESS. CURRENT WAS INTEGRATED OVER THE COURSE OF A SINGLE CV CYCLE (N=2)
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Cyclic Voltammetry (CV) Cyclic voltammograms were obtained for various platinized surface when potential was swept between ‐0.6 V and +0.5 V. The absolute value of the current was integrated over a single CV cycle to measure charge capacity (Fig. 4A). The charge capacity was observed to increase with increasing duration of platinization (Fig. 4B). Electropolymerization of PPy/Fluorescein films The same electropolymerization voltage and duration were applied to each of the electrode groups, resulting in drastically different currents (Fig. 5A). This is expected as lower impedance from the rougher electrodes allows higher electrical current to flow. Integrating the current over the duration of electropolymerization yielded charge accumulations, which was found to be proportional to the duration of platinization (Fig. 5B, R2 = 0.99).
A
B
FIG. 5 (A) TYPICAL ELECTROPOLYMERIZATION CURVES FOR PPY/FLUORESCEIN DEPOSITION ON DIFFERENT ELECTRODE SURFACES. THE SEPARATE CURVES INDICATE THE DURATION OF PLATINUM DEPOSITION ON THE GOLD ELECTRODE SURFACE. (B) CHARGE ACCUMULATION DURING ELECTROPOLYMERIZATION OF PPY/FLUORESCEIN FILMS ON ELECTRODE SURFACES OF VARYING PT‐BLACK THICKNESS (N=12). THESE VALUES WERE OBTAINED BY INTEGRATING THE CURRENT CURVES FROM ELECTROPOLYMERIZATION
Fluorescein Release In our experiments, fluorescein was released by two different mechanisms: active release trigged by electrical stimulation or passive release mediated by diffusion and ion exchange in solution. In this regard, release from the electrical stimulation group inherently releases drug from a diffusive mechanism as well, whereas the diffusion group has no release from electrical stimuli. Therefore, to distinguish the difference between these two mechanisms, the amount of release from the diffusion group was subtracted from the amount of release from the electrical stimulus group. This resulted in three distinct release groups: stimulus, diffusion, and isolated stimulus. The fluorescein release through passive diffusion was significantly less than the group subjected to the electric command stimulus, and the fraction of the diffused drug from the total drug release ranged from 5.2 – 14.7% across the different platinized surfaces. The electrically stimulated release (isolated) showed an increase as the platinization duration increased (Fig. 6A). A linear relationship was found between the isolated stimulated release amount and capacitance of the substrate electrodes, which is proportional to the electrode area, (Fig. 6B). The isolated stimulus release was normalized to represent the fraction of release per charge used during electropolymerization (Fig. 6C). The charge used during the polymerization was approximately proportional to the amount of polymer film formed, and this can be extended to illustrate the fraction of release per amount of
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polymer. Within each of the three release conditions, release per charge accumulation increased for increasing durations of platinization on the electrode surface.
A
C
B
FIG. 6 (A) FLUORESCEIN RELEASE FROM PPY/FLUORESCEIN FILMS ON ELECTRODE SURFACES OF VARYING PT‐BLACK THICKNESS (N=6 PER GROUP). THE ELECTRICAL STIMULUS APPLIED WAS A 10 SECOND PULSE AT ‐2.0 V. THE DIFFUSION GROUP WAS ALLOWED TO SIT IN SOLUTION IN THE ELECTROCHEMICAL CELL FOR AN EQUAL PERIOD OF TIME. THE RELEASE FROM THE ISOLATED STIMULUS WAS CALCULATED FROM THE DIFFERENCE. (B) FLUORESCEIN RELEASE FROM ISOLATED STIMULUS GROUP (N=6) FROM PPY/FLUORESCEIN FILMS ON ELECTRODE SURFACES OF VARYING PT‐BLACK THICKNESS AS A FUNCTION OF AVERAGE CALCULATED EQUIVALENT CAPACITANCE (N=4). (C) FLUORESCEIN RELEASE PER CHARGE DEPOSITION DURING ELECTROPOLYMERIZATION OF PPY/FLUORESCEIN FILMS FROM ISOLATED STIMULUS GROUP (N=6)
Charge injection during electrically stimulated release was also analyzed. A representation of efficiency can be realized by looking at drug released per charge injected. Although the electrical voltage stimulus was the same for each electrode, more charge was injected during this stimulus in the electrodes with rougher platinum surfaces (Fig. 7A). Additionally, when drug release was normalized per charge injected during the stimulus, much more fluorescein was released from the electrodes with rougher platinum surfaces for the same amount of charge passed (Fig. 7B). Specifically, the film grown on platinized surface (platinized for 200 s) electrically released 29.8 times more fluorescein than that grown on non‐platinized surface per mC of charge injection. More release with an equivalent amount of charge means higher efficiency and lower power consumption.
A
B
FIG. 7 (A) CHARGE INJECTION DURING ELECTRICAL RELEASE STIMULUS OF ‐2.0 V FOR 10 SECONDS FOR EACH OF THE DIFFERENT ELECTRODE SURFACES (N=3). (B) DRUG RELEASE FROM ‐2.0 V PULSE FOR 10 SECONDS PER CHARGE INJECTED FOR ISOLATED STIMULUS GROUP (N=6 FOR RELEASE CONCENTRATION, N=3 FOR CHARGE)
Discussion There are many factors to be considered in the optimization of an electrically controlled drug release system. These
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include maximizing drug storage capacity per unit area and per amount of polymer as well as improving the release efficiency for maximal clinical efficacy. This study illustrates the effect of increased surface area on both the amount and efficiency of drug release. As illustrated by the scanning electron micrographs, the surface morphology changes substantially as platinum deposition time increases. Less rough platinum surfaces show an increased surface area from the bare gold, but do not acquire the nodular macrostructure exhibited by the thicker platinum black surfaces. The increase in surface area as the platinization time increases is evidenced by the charge capacity analyses and the equivalent circuit capacitance values. As surface area increases with the thicker platinum black electrode surfaces, drug release increases accordingly. Particularly interesting is the increase of drug release per deposition charge as the platinization time increase (Fig. 6), suggesting that more drug is incorporated in the polymer film grown on rougher surfaces. While the electropolymerization voltage is identical for every electrode, the deposition currents are much higher on the rougher electrode surfaces. These higher charge deposition values suggest that the increased surface area causes more polymer film to be deposited, incorporating more drug. The trends in release per charge injection have intriguing implications. It is apparent that, due to the reduced impedance, the increase in surface area from rougher platinum surfaces results in higher charge injection upon application of the release voltage stimulus. More importantly, the PPy/fluorescein films on the rougher platinum surfaces also release more drug for the same amount of charge passed, suggesting that the rougher surfaces increase the efficiency of drug delivery. Thus, for a desired quantity of drug to be released, this suggests that drug delivery will require less charge to be passed into the electrode and subsequently into tissue from rougher electrode surfaces. This will reduce the potential tissue damage that charge injection could lead to. Additionally, the incorporation of Pt‐black as the specific electrode substrate has been shown to reduce electrode impedance in neural stimulation, allowing the same amount of current to be passed through the electrode at much lower potential (Desai, Rolston et al. 2010). Lower potential is also desired from chronic electrode‐tissue interface stability point of view. Inherent to conducting polymer release systems, the release mechanism by which the drug leaves the film is comprised of both electrical and diffusive driving forces. During the polymerization and dopant incorporation, some negatively charged species are tightly bound to the positive charged polymer backbone as dopants, while others are loosely adsorbed on the film surface. The drug molecules electrostatically bound to the polymer backbone are released only when cathodic currents remove the positive charges on the backbone, while the adsorbed drug leaks from the conducting polymer film down its concentration gradient via Fickian diffusion. A desirable electrochemical drug delivery system will minimize the diffusion driven drug release in an effort to release the drug in a highly controllable fashion, mediated primarily by the electrical command stimulus. In the current system, the substrate with highest surface area has a 14.7% diffusion driven drug release. This phenomenon is drug dependent. Fluorescein has low water solubility and is therefore difficult to wash off the polymer surface using aqueous media after the polymerization. A more thorough wash with good solvents could remove most of the adsorbed fluorescein and reduce the fraction of diffusion driven drug release. Conclusions Electroactive conducting polymers hold great promise for the development of highly controllable drug release systems. The advantages of increased surface roughness include increased drug load per area, increased release efficiency per charge injection, and low impedance. Diffusion and electrochemical cues play considerable roles in mediating drug release from the film, with the latter being predominant. These findings can be applied to maximize the delivery of other similar drugs of clinical or experimental relevance. ACKNOWLEDGMENT
We would like to acknowledge Nicolas Alba, William Stauffer, and Xiliang Luo for their insightful advices. The authors acknowledge the facilities, scientific and technical assistance of the Materials Micro‐Characterization Laboratory of the Department of Mechanical Engineering and Materials Science, Swanson School of Engineering, University of Pittsburgh. This research is funded by NSF Grant 0729869 and NSF Career Award DMR‐0748001.
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The effect of polypyrrole with incorporated neurotrophin‐3 on the promotion of neurite outgrowth from auditory neurons. Biomaterials 28:513‐523. [23] Richardson RT, Wise AK, Thompson BC, Flynn BO, Atkinson PJ, Fretwell NJ, Fallon JB, Wallace GG, Shepherd RK, Clark GM, OʹLeary SJ (2009) Polypyrrole‐coated electrodes for the delivery of charge and neurotrophins to cochlear neurons. Biomaterials 30:2614‐2624. [24] Shain W, Spataro L, Dilgen J, Haverstick K, Retterer S, Isaacson M, Saltzman M, Turner JN (2003) Controlling cellular reactive responses around neural prosthetic devices using peripheral and local intervention strategies. IEEE Trans Neural Syst Rehabil Eng 11:186‐188. [25] Zhou Q‐X, Miller L, Valentine J (1989) Electrochemically controlled binding and release of protonated dimethyldopamine and other cations from poly( N‐methyl‐pyrrole)/polyanion composite redox polymers. J Electroanal Chem 261:147‐164. [26] Hepel M, Mahdavi F (1997) Application of the Electrochemical Quartz Crystal Microbalance for Electrochemically Controlled Binding and Release of Chlorpromazine from Conductive Polymer Matrix Microchemical Journal 56:54‐64. [27] Desai S, Rolston JD, Guo L, Potter SM (2010) Improving impedance of implantable microwire multielectrode arrays by ultrasonic electroplating of durable platinum black. Front Neuroengineering 3:1‐11. [28] Cui X, Martin D (2003) Fuzzy gold electrodes for lowering impedance and improving adhesion with electrodeposited conducting polymer films. Sensor Actuat A‐Phys 103:384‐394. [29] Orazem ME, Tribollet B (2008) Electrochemical Impedance Spectroscopy, Electrochemical Society Series. John Wiley & Sons, Inc, Hoboken, NJ. Michael S. Freedman received his B.S.E. in Bioengineering, B.S. in Chemistry, and B.A. in Music from the University of Pittsburgh in May 2010, and M.Phil. in Bioscience Enterprise from the University of Cambridge in July 2011. He is currently pursuing his M.D. and the University of California, San Francisco. His research interests include biocompatible conducting polymers and drug delivery. X. Tracy Cui received her B.E. in Polymer Materials and Chemical Engineering and M.S. in Biophysics from Tsinghua University in Beijing, China. She did her Ph.D. in the Macromolecular Science and Engineering Center of the University of Michigan working on surface modification of neural probes for neural recording from CNS. Immediately after graduation in 2002, she went to work for Unilever Research as a research scientist working on skin biomaterials and skin tribology. In September 2003, She joined the faculty of Department of Bioengineering at Pitt and is the co‐director of the neural engineering track. Her main research interests are: Neural Electrode / Tissue interface, Neural Tissue Engineering, Conducting Polymer Based Biosensors, Actuators and Controlled Drug Release System.
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