Jessica Alves Marins

Francoise Giulieri

Bluma Guentther Soares

Georges Bossis

Jéssica Alves Marins

Françoise Giulieri

Bluma Guenther Soares

Hybrid polyaniline-coated sepiolite nanofibers for electrorheological fluid applications

Keywords: electrorheology, nanofibers, polyaniline

Introduction

Electrorheological fluids ERF are colloidal suspensions of polarizable organic or inorganic particles dispersed in a nonconducting liquid such as silicone oil, kerosene, paraffin, vegetable oil or halogenated hydrocarbon [START_REF] Hao | Electrorheological suspensions[END_REF][START_REF] Kim | Emulsion polymerized polyaniline synthesized with dodecylbenzenesulfonic acid and its electrorheological characteristics: Temperature effect[END_REF]. Under the action of an electric field, the suspended particles in a non-polar fluid align along the field direction and form fibril-like microstructures which drastically increase the apparent viscosity and yield stress of the fluid. This behavior characterizes the electrorheological effect [START_REF] Gehin | Electrorheological properties and microstructure of silica suspensions[END_REF][START_REF] Jiang | Structure Parameter of Electrorheological Fluids in Shear Flow[END_REF], whose effect can be modeled by the Bingham [START_REF] Kor | The electrorheological response of elongated particles[END_REF] or Cho-Choi-Jhon model [START_REF] Kim | Emulsion polymerized polyaniline synthesized with dodecylbenzenesulfonic acid and its electrorheological characteristics: Temperature effect[END_REF]. Many kinds of particles are used in the preparation of ERF, like cellulose, silica, zeolites, starch and titania [START_REF] Cheng | Synthesis and electrorheological characteristics of sea urchin-like TiO2 hollow spheres[END_REF]. These particles # # Corresponding author: Jéssica A. Marins: e-mail: jessica.amarins@gmail.com feature the fluid as hydrous ERF. The water acts as an additive, but this system presented some disadvantages like evaporation of water and electric breakdown. More recently anhydrous ERF have been studied to improve their performance and the most common particles are made of conducting polymer like polyaniline, copolyaniline and polypyrrole [START_REF] Kim | Electrorheological and dielectric properties of polypyrrole dispersions[END_REF].

Polyaniline (PAni) presents good electrical conductivity, which can be controlled through the pH value, easiness of preparation, relatively low density, stability to the heat and to the air, and low production costs. These characteristics made polyaniline to be considered one of the most versatile and the cheapest conducting polymer material, for using in ERF. However after many investigations the use of polyaniline did not obtain great success because of the low yield stress, colloidal instability and mainly due to the too high current density of the corresponding fluids. In order to solve these problems it was proposed to coat polyaniline on inorganic particles or insulating polymer. Choi et al. [START_REF] Choi | Synthesis and electrorheology of emulsion intercalated PAni-clay nanocomposite[END_REF], Lim et al. [START_REF] Lim | Improved electrorheological effect in polyaniline nanocomposite suspensions[END_REF] and Song et al. [START_REF] Song | Intercalated conducting polyaniline-clay nanocomposites and their electrical characteristics[END_REF] prepared PAni/Clay composites, which presented irregular morphology and good ER effect. Different PAni/silica composites have also been employed in ERF. For instance, silica nanoparticle decorated with conducting polyaniline fibers was used in ERF by Liu et al. [START_REF] Liu | Silica nanoparticle decorated conducting polyaniline fibers and their electrorheology[END_REF], but a better ER effect was obtained with pure PAni fiber whereas the composite presented instability in the chain-like structure as a function of shear rate. The same group prepared PAni/nanosilica nanocomposites, and in this case the nanocomposites performed better [START_REF] Liu | Fabrication of semiconducting polyaniline/nano-silica nanocomposite particles and their enhanced electrorheological and dielectric characteristics[END_REF]. PAni coated with insulating polymer as: polystyrene (PS) microspheres with PAni [START_REF] Liu | Smart monodisperse polystyrene/polyaniline core-shell structured hybrid microspheres fabricated by a controlled releasing technique and their electro-responsive characteristics[END_REF] has been also investigated. This system presented improved yield stress with a linear behavior with the electrical field strength.

The present work deals with the development of sepiolite coated with polyaniline and the evaluation of this new hybrid material as an effective component for electrorheological fluids. The motivation of this present work is based on foreknowledge that elongated particles performs better on ER properties than spherical particles, because the dipole moment is larger for elongated particles than for spherical particles of the same size and polarizability [START_REF] Ramos-Tejada | Electrorheology of suspensions of elongated goethite particles[END_REF]. An approaching system based on a PAni coating of aluminosilicate nanotubes of aspect ratio of about ten was recently explored but it did not gave higher ER effect than other systems based on PAni [START_REF] Zhang | Fabrication of semiconducting polyaniline-wrapped halloysite nanotube composite and its electrorheology[END_REF] Here we used sepiolite fibers which have a larger aspect ratio (1-5 m in length and 20-40 nm in diameter) and no conductivity. The sepiolite consists of mineral clay of hydrated magnesium silicates. Additionally sepiolite fiber surface is covered with silanol groups spaced 5 Ǻ apart, and external channels that are covered on one or two sides with Mg(OH2)2. The internal channels are covered with Mg(OH2)2 on two sides and with Si-O-Si on the other two sides, these channels are filled with zeolitic water [START_REF] Rautureau | Structural-analysis of sepiolite by selected area electron-diffraction -relations with physicochemical properties[END_REF][START_REF] Serna | Folding in sepiolite crystals[END_REF].

The surface silanol groups allow building hydrogen bonding with PAni without the needs to add compatibilizing agent.

For the development of a good coating of polyaniline on sepiolite surface, two different synthetic methods were used; the first one is called solid-solid and bulk polymerization, it consists of a mechanochemical adsorption that occurs between powders in the solid state [START_REF] Bekri-Abbes | Characterization and AC conductivity of polyaniline-montmorillonite nanocomposites synthesized by mechanical/chemical reaction[END_REF][START_REF] Bekri-Abbes | Solid-state synthesis and electrical properties of polyaniline/Cu-montmorillonite nanocomposite[END_REF]. The second method is the slurry polymerization. This kind of polymerization is performed in two phases, the first one consisted of the monomer and initiator solution and the second phase is formed when the polymer chains grows, and lose their affinity with the solvent resulting in polymer precipitate. Three concentration were tested 90:10, 70:30 and 50:50 weight ratio sepiolite:aniline. Dielectric properties were investigated in correlation with ER effect. The flow curve and dynamic viscoelastic tests were made as well as strain and frequency sweeps. The pure PAni fiber was analyzed for comparison [START_REF] Marins | A facile and inexpensive method for the preparation of conducting polyanilineclay composite nanofibers[END_REF].

Experimental section

Materials

Aniline (Ani) (analytical grade), ammonium peroxydisulfate (APS) (analytical grade), ortho phosphoric acid (Ph) (analytical grade), ammonium hydroxide NH4OH (analytical grade) all from Sigma-Aldrich and sepiolite (S9 grade, Tolsa) were used without purification; a previous method of disaggregation was made using 10% of sepiolite in water was submitted to an ultrasound treatment for 40 min operating at 28% amplitude pulse 2/2sec and after this solution was dried at 100 °C. De ionized water (18.2 M .cm) was employed in all experiments

Synthesis of PAni/Sepiolite by bulk polymerization

Sepiolite was milled in a mortar during 15 minutes Then the aniline was slowly added and, after obtaining a visually homogeneous powder, the H3PO4 was added. When the medium became clear the APS was added and mixing was continued until a light pink color appeared. The reaction recipes are indicated in the Table 1. The sepiolite fibers aniline, phosphoric acid and APS were periodically mixed until the formation of a dark green powder. The dark green powder was poured into acetone, filtered and re-dispersed in aqueous solution containing 0.1M of NH4OH, kept under agitation for 4 h and dried at 70° C.

Synthesis of PAni/Sepiolite by slurry polymerization

Different amounts of sepiolite were dispersed in water (150 mL) using an ultrasound tip. Then a mixture of aniline (0.001 mol) and H3PO4 (0.0013 mol) was dissolved in 50 mL of water, and the resulting dispersion was ultrasonicated for 20 min with the help of a Vibracell 75041 -Bioblock scientific ultrasonic apparatus equipped with an ultrasound tip and operating at 28% amplitude pulse 2/2 sec. After 24 hours without stirring, 10 mL of an aqueous solution containing 0.0013 mol of APS were quickly added and the reaction medium was submitted to an ultrasound treatment for 20 min operating at 28% amplitude pulse 2/2sec. The polymerization was carried out at room temperature without stirring for different times (Table 1). The dark green precipitate was poured into acetone, filtered and re-dispersed in aqueous solution containing 0.1M of NH4OH, kept under agitation for 4 h and dried at 70° C.

Characterization

The micrographs of the sepiolite and polyaniline coated sepiolite were recorded from a JEOL-1400 transmission electronic microscope, operating at 90kV. A diluted dispersion of the particles in water was first obtained by sonication. This dispersion was deposited on an amorphous polymer coated-copper grid.

Fourier transformed Infrared spectra (FTIR) were recorded in Perkin-Elmer Paragon 1000 spectrometer. Sepiolite, PAni and their mixtures were characterized by diffuse reflection infrared spectroscopy (DRIFT, minidiff plus diffuse reflectance acquired from Eurolabo). The powder mixed with KBr was placed in the cup and the background spectrum of KBr was subtracted. All transmittance spectra were taken at a resolution of 4 cm -1 for 64 scans from 4000 to 400 cm -1 .

Thermo-gravimetric analysis was performed in a TA Instruments Q50 V20.10 Build 36 analyzer operating at a heating rate of 20° C/min, under nitrogen atmosphere (balance gas: nitrogen 40.0 mL/min and sample gas: nitrogen 60.0 mL/min)

The TGA profiles were recorded in the temperature range 50-700° C. The weight of the sample used was about 9-11 mg in all the cases.

To determine the dielectric constant and conductivity, a pellet was made from the powder with a surface area 1.33x10 -4 m 2 and thickness 4x10 -4 m. The measure was made with an AC impedance bridge using a Solartron SI 1260 gain phase analyzer, interfaced to a Solartron 1296 dielectric interface. The measurements were carried out in a frequency range of 0.01 Hz to 100 kHz with 2V oscillating voltage.

Rheological measurements were performed using the Anton Paar Instruments Physical MCR 301, rheometer with electrorheological accessory, (Generator Model 609E-6 High voltage amplifier TREK with Multimeter Hameg Instruments -AC) plate-plate geometry (PP50/E-SN12613 gap 1 mm). The suspensions for ER measurements were prepared by dispersing pure PAni, SP70:30s and SP50:50s at 10% vol. in castor oil, from Sigma Aldrich, with the help of ultrasonic apparatus operating at 20% amplitude for 2 min.

Results and discussion

PAni/Sepiolite fibers were obtained by aniline polymerization in the presence of sepiolite. This method allowed the interfacial interaction between the aniline and the sepiolite surface. The schematic diagram of the polymerization of the aniline is shown in the Figure 1. The -OH groups at the sepiolite surface interact with the aniline monomer, through hydrogen bond between -NH2 of aniline and -OH of sepiolite. This same interaction is reported in the study of sepiolite with polyimide [START_REF] Yu | Polyimide/sepiolite nanocomposite films: Preparation, morphology and properties[END_REF] and the other studies of polyaniline coated cellulose fibers [START_REF] Hu | Flexible Electrically Conductive Nanocomposite Membrane Based on Bacterial Cellulose and Polyaniline[END_REF] c at 3622 and 3555 cm -1 are associated with the coordinated water ν-OH [START_REF] Ruiz-Hitzky | Molecular access to intracrystalline tunnels of sepiolite[END_REF]. These bands disappeared in the SP70:30b and SP50:50b, samples, indicating that sepiolite is completely coated by PAni chains at these compositions. The SP90:10b sample presents these bands because the amount of PAni is not enough to coat the sepiolite fibers. The band d and e at 1576 and 1497 cm -1 are ascribed to the quinoid and benzonoid rings respectively, related to the polyaniline component [START_REF] Marins | Structure and properties of conducting bacterial cellulose-polyaniline nanocomposites[END_REF]. These bands are very weak in SP90:10b. The band f at 1307cm -1 is attributed to the C-N + bond corresponding to the π-electron induced in the polyaniline chain by protonation [START_REF] Bekri-Abbes | Characterization and AC conductivity of polyaniline-montmorillonite nanocomposites synthesized by mechanical/chemical reaction[END_REF][START_REF] Wu | Reaction of aniline with FeOCl -Formation and ordering of conducting polyaniline in a crystalline layered host[END_REF]. The band g at 1209 cm -1 is related to the Si-O bond of sepiolite. This assignment is apparent in the SP90:10b sample, but less clear in SP70:30b and SP50:50b These results are hints that the sepiolite was not completely coated in the SP90:10b sample or that the polymerization of aniline produced oligomers.

The TEM micrographs of PAni/sepiolite and pure sepiolite are illustrated in Figure 2b. Sepiolite presents the TEM pictures of the fibers. Their cross section is rectangular about 20x40 nm and their average length is about one micron. The SP90:10b sample exhibits slight agglomerates of fibers but it was not possible to observe the polyaniline coating the sepiolite surface, as also indicated in the FTIR results. SP70:30b and SP50:50b images show presence of large agglomerates constituted by polyaniline and sepiolite fibers. These images indicate that the method by bulk polymerization is not appropriate to obtain the pure fibers coated by polyaniline, and not interesting to prepare the electrorheological fluids.

PAni/Sepiolite by slurry polymerization

The slurry polymerization was used to improve the dispersion of sepiolite and to help the coating of the fibers by polyaniline. As indicated in the Table 1 the amount of polyaniline in the composite is very small when 10% of aniline is employed. Figure 3a shows the FTIR spectra of SP composites. The SP70:30s sample displays the band a at 1658 cm -1 and band d at 1000 cm -1 which are typical of sepiolite and the bands b and c at 1584 and 1497 cm -1 are ascribed to the quinoid and benzonoid rings [START_REF] Marins | Structure and properties of conducting bacterial cellulose-polyaniline nanocomposites[END_REF] respectively, which are typical of polyaniline. The presence of the typical bands of the sepiolite indicates that the fiber was not completely coated by polyaniline. In the SP50:50s sample, the bands related to the sepiolite are not so evident indicating that the PAni coating was more effective. The images shown in Figure 3b corroborate the FTIR results. It is possible to see in the micrograph the presence of several nanoparticles of PAni well adhered to the sepiolite surface along all fiber surface. The amount of polyaniline in these composite was estimated by TGA analysis, and corresponds to 14 and 46 %wt. of PAni for the SP70:30s and SP50:50s samples, respectively.

Electrorheological properties

Preliminary tests were performed to determine the electrorheological parameters. To measure the electrorheological properties an electric field (0.5 kV/mm) was applied at different frequencies (f) (10 Hz, 5 kHz and 15 kHz) and the current density was measured in each case. Based on the results indicated in the Table 2, at large frequencies the current density (j) was high and the shear stress small. For this reason, all measurements were performed at 10 Hz corresponding to the largest yield stress τy and the smallest current density and the electric field range was 0-2 kV/mm. Only the SP50:50s sample was studied in detail and the polyaniline fibers were used for comparison, because, as presented in Table 2, the SP70:30s sample presented a yield stress three times lower than the SP50:50. 4 presents the curves in the control shear rate (CSR) mode for dispersions containing SP50:50s under different electric field strengths. This fluid was submitted to an AC (10 Hz) electric field (E) at 0, 0.5, 1 and 1.5 kV/mm and analyzed the dependence of shear stress with shear rate at room temperature, within the shear rate range of 0.001-1000 s - 1 Without an external electric field, the dispersions containing SP50:50s presented shear-thinning phenomenon. Similar behavior was observed by J Yin et al [START_REF] Yin | Electrorheological fluids based on nano-fibrous polyaniline[END_REF] using fluids based on nano-fibrous PAni. Differently the composites with PAni/ClayMMT studied by Choi et al [START_REF] Choi | Synthesis and electrorheology of emulsion intercalated PAni-clay nanocomposite[END_REF] with 20%wt and Lim et al [START_REF] Lim | Improved electrorheological effect in polyaniline nanocomposite suspensions[END_REF] with 15% -wt presented a typical Newtonian behavior.

In the presence of an electric field the dispersions containing SP50:50s still presented the shear-thinning phenomenon but on a limited flow range, like plastic materials. The yield stress τy increases with E, from τy = 192 Pa at 0.5 kV/mm, to τy = 400 Pa at 1 kV/mm and τy = 707 Pa. at 1.5 kV/mm. At high shear rates (500-1000 s -1 ) the slope of the flow curve with applied field was observed to be much higher than that one in the absence of field. This last observation indicates that, unlike the prediction of the Bingham model, the stress needed to break the aggregates increases with the shear rate.

This behavior may be attributed to the change of structure of these aggregates which becomes less compact and then occupy a larger effective volume fraction when the shear rate increases.

τ y ∝ E α
According to the literature, α = 2, corresponds to the polarization model and α equal 1.5 to the conduction model [START_REF] Liu | Conducting Material-incorporated Electrorheological Fluids: Core-shell Structured Spheres[END_REF][START_REF] Wu | Dielectric and conduction effects in non-Ohmic electrorheological fluids[END_REF] A linear relation between the yield stress τy and the electric field can be the signature of the polarization of polar molecules at the surface of the particles, as found in the giant electrorheological effect [START_REF] Vemuri | New analysis of yield stress on giant electrorheological fluids[END_REF]. This behavior is also often attributed to the saturation of the local electric field due to the exponential increase of conductivity in the gap between two particles [START_REF] Liu | Conducting Material-incorporated Electrorheological Fluids: Core-shell Structured Spheres[END_REF][START_REF] Klingenberg | The small shear rate response of electrorheological suspensions .2. Extension beyond the point-dipole limit[END_REF]. Tsuda et al. found a slope of 1.8 for spherical particles of aluminum-borate, but for whiskers of the same composition, the slope decreased to 1.3 [START_REF] Tsuda | Electrorheological behavior of whisker suspensions under oscillatory shear[END_REF]. Also, in the study reported by .In the linear polarization model the force between two dipoles aligned in the direction of the field and separated by a distance L is given by:

2 E 4 0 f 1 6m F 4 L = πε ε (1)
with the dipolar moment of a fiber given by:

0 f 0 m 3V E = β ε ε (2)
where V=Lπd 2 /4 and β is a function of the permittivity and of the conductivity of the two components; for a fiber like particle we obtained:

( ) ( ) 2 2 2 p f 0 2 f z p z MW 1 3( (1 n ) n ) 1   σ -σ + ωτ β =     σ - + σ + ωτ   (3) With z f z p f 0 MW f z f z p (1 n ) n and (1 n ) n -ε + ε ε τ = τ = σ -σ + σ
σp particle conductivity, σf fluid conductivity, εp absolute dielectric constant of particle, εf absolute dielectric constant of fluid and ω the angular frequency. The depolarization factor along the main axis, nz, can be approximated by the one of an ellipsoid:

z 2 2 1 1 n 1 arg cos h(r) r 1 r 1   = -   - - 
 where r=L/d is the aspect ratio.

Actually the Eq.( 1) is not well adapted to fibers since it supposes that the dipoles are located at the center of the fiber whereas they are spread uniformly on the particle. A better approximation in this case is to consider the interaction between point charges located at the extremity of the fibers with an equivalent charge: Q=m/L where L is the length of the fiber [START_REF] Bossis | Magnetorheology: Fluids, Structures and Rheology, Ferrofluids:Magnetically Controllable Fluids and Their Applications[END_REF]. The force between two fibers is attractive when the shift between their centers is larger than L/2 (cf. Figure 7).

The main attractive force is the one between the charges located in the points B1 and A2, given by: F=Q 2 /(4πε0ε1r 2 ). We suppose that the fibers will slip along each other before to separate. At the end point the attractive force will be along the x axis and its magnitude will be: Expressing m from Eq.( 2) we obtain the final form of the average force between two fibers: then,

2 E 2 2 0 f 1 m 1 F 4 L d = πε ε (4)
2 2 2 E 0 f 9 F d E 64 π < >= ε ε β (5)
where β 2 is given by Eq. ( 3)

We note here that the force is just proportional to the square of the diameter of the fiber, whereas if we were using Eq.

( 1)-( 2) we would get an extra factor 6(d/L) 2 , which would decrease a lot the estimation of the electric force.

The hydrodynamic force which will pulls apart the two fibers can be approximated by the friction coefficient of a fiber times the difference of velocity, v L ∆ = γ ɺ . The friction coefficient, ξ, of a fiber in a transverse flow is given by Batchelor [START_REF] Batchelor | Slender-body theory for particles of arbitrary cross-section in stokes flow[END_REF] :

S f 2 2 E 0 f F 256 L Mn F 9 E d η γ   = =   ε ε β   ɺ ( 6
)
where ηf is the viscosity of the suspending fluid, and εf the dielectric constant of the suspending fluid. [START_REF] Wu | Dielectric and conduction effects in non-Ohmic electrorheological fluids[END_REF][START_REF] Marshall | Effects of electric-fields on the rheology of non-aqueous concentrated suspensions[END_REF][START_REF] Volkova | Shear banded flows and nematic-to-isotropic transition in ER and MR fluids[END_REF] As shown in the Figure 6 the exponent of the field dependence is α = 1.24 for SP50:50s sample, so the exponent of the field in Eq.( 6) should be changed accordingly . In the calculation for SP50:50s sample was used ε0 = Viscoelastic tests were performed through strain sweep at strain range 0.01-5% and angular frequency (20 rad.s -1 ).

Figure 9a shows the storage modulus and the loss modulus as a function of strain for pure PAni and SP50:50s at a field E = 2 kV/mm The fluid of PAni fibers presented a purely viscous behavior in the absence of an electric field, but the sepiolite coated by polyaniline (SP50:50s) presented a weak contribution (95 Pa) for the storage modulus in absence of field. Both samples (pure PAni and SP50:50s), in the presence of an electric field presented a solid viscoelastic behavior with G' larger than G". The sample SP50:50s has a linear viscoelastic region smaller than pure PAni the region is 0.01 to 0.1% for pure PAni and 0.01 to 0.04% for SP50:50s but the magnitude of the field induced shear modulus is much larger for the SP50:50s sample.

Figure 9b represents the results, for fluids containing 10% vol. pure PAni fibers and SP50:50s, for a frequency (ω) sweep performed at 0.03% of strain, under electric field of 2kV/mm. Here too we see that under the same field, G' of SP50:50s fluid is an order of magnitude larger than G' of pure PAni fluid. We note that for ω around 0.3 rad/s there is a small dip of G' and a maximum of G" for both compounds. This phenomenon is likely related to some structural relaxation time of the columns of fibers. Then there is a small increase of G' and G" with ω for the SP50:50 whereas it remains constant for the pure PAni sample. With the increase of field strength the values of the storage and loss modulus increase strongly. The slopes of G' versus the electric field are given in the Table 3. It is noted that the slope of G' for the SP50:50s suspension was approximately the same as the slope of the yield stress versus field (1.24 compared to 1.28), but they are more different for the pure PAni suspension (1.32 compared to 1.52)

Conclusion

This work presented two different methods to prepare the polyaniline-coated sepiolite, denoted bulk and slurry polymerizations. The first method was effective for achieving good yield of polyaniline in all sepiolite /polyaniline compositions but resulted in the formation of aggregates of sepiolite embedded by polyaniline. Contrarily, the slurry polymerization of aniline in the presence of sepiolite gave rise to nice nanocomposites with PAni nanoparticles well adhered to the sepiolite surface. The composition to achieve the coating of sepiolite with polyaniline in larger extent corresponds to 46 -wt% of PAni, as indicated by FTIR and TEM and quantified by TGA analysis.

The best electrorheological response was obtained with suspensions of SP 50:50s sample, which contains sepiolite coated with 46 wt% of PAni. In fact, this suspension presented better ER effect than that constituted by pure PAni fibers, with a storage modulus, G'= 536 kPa for the composite SP50:50s and only 56 kPa for pure PAni fiber suspension at 2 kV/mm. These values are well above those published in previous papers for polyaniline based particles [START_REF] Cho | Synthesis and electrorheological characteristics of polyaniline-coated poly(methyl methacrylate) microsphere: Size effect[END_REF][START_REF] Liu | Core-Shell Structured Semiconducting PMMA/Polyaniline Snowman-like Anisotropic Microparticles and Their Electrorheology[END_REF]. The value of the yield stress of about 1 kPa at 2kV/mm for SP50:50s suspension is the same as the one obtained by Lim et al. [START_REF] Lim | Improved electrorheological effect in polyaniline nanocomposite suspensions[END_REF] for a coating of PAni on montmorillonite clay platelets. We also note that an anisotropic shape (either needle or platelet) increases considerably the yield stress compared to spherical shape where a yield stress of about 300 Pa was obtained for the same field on a PAni coating of silica [START_REF] Liu | Silica nanoparticle decorated conducting polyaniline fibers and their electrorheology[END_REF]. These results highlight the importance of developing hybrid polyaniline-based nanoparticles with elongated structures to obtain ER fluids with better performance and open new possibilities of synthesizing other hybrid materials with tuned morphology for electro-rheological fluids with better ER performance than those constituted by the pure components. In this context, the synthesis of other PAni-based materials with elongated structures and the evaluation of their ER performance are in progress and it will be subject of future publications.

Figure 1 .

 1 Figure 1. Schematic diagram of the formation of polyaniline at the surface of sepiolite

Figure 2 .

 2 Figure 2. FTIR spectra (a) and TEM micrographs with a scale of 200 nm (b) of sepiolite, SP90:10b, SP70:30b and SP50:50b by bulk polymerization

Figure 3 .

 3 Figure 3. FTIR spectra (a) of sepiolite, PAni, SP70:30s and SP50:50s and TEM micrographs (b) of PAni, SP50:50s and SP70:30s by slurry polymerization

Figure 4 .

 4 Figure 4. Shear stress as a function of shear rate for SP50:50s suspension under different field strengths

  Cheng et al., they noted that the change of morphology of the TiO2 particles influence the structuring process under an electric field[START_REF] Cheng | Synthesis and electrorheological characteristics of sea urchin-like TiO2 hollow spheres[END_REF]. Yin et al. obtained the range of α = 1.8-1.2 for the PAni fibers made with L-camphorsulfonic acid. And the authors observed a decreasing of the yield stress as a function of electrical field slope with increasing the acid concentration[START_REF] Yin | Electrorheological fluids based on nano-fibrous polyaniline[END_REF]. In this work both samples, SP50:50s and PAni, have a similar morphology and the same volume fraction, so a change of slope cannot be directly related to the change of morphology. Still the slopes are different with α=1.52 for PAni fiber, this correspond to the conduction model and α=1.24 for the polyaniline coated sepiolite (SP50:50s) indicating that the presence of insulated materials interfered in the conduction model for PAni.

Figure 5 .

 5 Figure 5. Yield stress as a function of electric field at shear rate (0.1s -1 ) for SP50:50s and PAni suspensions at volume fraction Φ=10%

Figure 6 .

 6 Figure 6. Relative dielectric constant (a) and conductivity (b) as a function of frequency obtained from SP50:50s pellet with the correction of volume fraction

Figure 7 .

 7 Figure 7. Model of interaction between two fibers

  ɺ and the Mason number for fibers reads:

2

 2

8 .

 8 85 x10 -12 , ε f ¿ = 3.8 ε0, εp= 137.47 ε0, σf= 10 -10 S/m, σp = 0.2 S/m, and an aspect ratio r = L/ d = 25, these values were measured at 10 Hz. Figure 8 shows the relative viscosity (η/ηf) as a function of Mason number for SP 50:50s suspension at different electric fields.

Figure 8 .

 8 Figure 8. Relative viscosity as a function of Mason number for SP50:50s suspension

Figure 9 .

 9 Figure 9. Storage Modulus, G' and Loss Modulus, G" versus strain at ω=20 rad/s (a) and as a function frequency at 0.03% of strain (b) for PAni and SP 50:50s suspension at 2kV/mm,

Table 1 .

 1 Amounts of reactive used to prepared polyaniline and the reaction time

	Sample	Sepiolite (g)	Ani (g)	H3PO4 (g)	APS (g)		Reaction time
						Bulk (b)	Slurry (s)
	SP90:10	0.9	0.1	0.14	0.33	72h	*
	SP70:30	0.7	0.3	0.42	0.98	24h	24h
	SP50:50	0.5	0.5	0.71	1.65	4h	4h
	* No product was obtained after 72h of reaction

Table 2 .

 2 Yield stress τy at different frequencies (f) at 0.5 kV/mm (AC)

	Sample	τy (Pa)	j(µA/mm 2 )	τy (Pa)	j(µA/mm 2 )	τy (Pa)	j(µA/mm 2 )
		10 Hz		5 kHz		15 kHz
	PAni	36	9.9x10 -3	15	0.17	10	0.19
	SP70:30s	67	6.5x10 -3	28	0.13	14	0.17
	SP50:50s	192	4.7x10 -3	82	0.05	30	0.16
	Figure

Table 3 .

 3 The storage modulus at different electric field The slope is obtained from the curve of the storage modulus as a function of the applied electric field in log-log scale

	Electric Field	PAni	SP50:50s
	E (kV/mm)		G'(kPa)
	0.0	0.01	0.08
	0.5	9	117
	1.0	23	202
	1.5	37	352
	2.0	56	536
	Slope *	1.32	1.28

*

Acknowledgments

This work was supported by Conselho Nacional de Desenvolvimento Científico e tecnológico -CNPq, Financiadora de Estudos e Projetos -FINEP and Fundação de Amparo à Pesquisa do estado do Rio de Janeiro -FAPERJ. They also thank S. Pergnotta (Centre Commun de Microscopie Appliquée, Université Nice-Sophia Antipolis) for her help with the electron microscopy.


Romain Mathieu
email: romainmath@yahoo.fr

Juan David

Ospina Arango

Véronique Beckendorf

Jean- Bernard Delobel

Taha Messai

Ciprian Chira

Alberto Bossi

Elisabeth Le Prisé

Stéphane Guerif

Jean-Marc Simon

Bernard Dubray

Jian Zhu

Jean- Léon Lagrange

Pascal Pommier

Khemara Gnep

Oscar Acosta

Renaud De Crevoisier

Nomograms to predict late urinary toxicity after prostate cancer radiotherapy

Keywords: late urinary toxicity, predictive models, nomograms, prostate cancer, radiotherapy

Objective:

To analyze late urinary toxicity after prostate cancer radiotherapy (RT): symptom description and identification of patient characteristics or treatment parameters allowing for the generation of nomograms.

Methods: 965 patients underwent RT in seventeen French centers for localized prostate cancer. Median total dose was 70 Gy (range, 65-80 Gy), using different fractionations (2 or 2.5 Gy/day) and techniques. Late urinary toxicity and the corresponding symptoms (urinary frequency, incontinence, Dysuria/decreased stream and hematuria) were prospectively assessed in half of the patients using the LENTSOMA classification. Univariate and multivariate Cox regression models addressed patient or treatment-related predictors of late urinary toxicity (! grade 2).

Nomograms were built up and their performance was assessed.

Results :

The median follow-up was 61 months. The 5-year (!grade 2) global urinary toxicity, urinary frequency, hematuria, dysuria and urinary incontinence rates were: 15%, 10%, 5%, 3% and 1%, respectively. The 5-year (! grade 3) urinary toxicity rate was 3%. The following parameters significantly increased the 5 year risk of global urinary toxicity (! grade 2): anticoagulant treatment (RR=2.35), total dose (RR=1.09), age (RR=1.06). Urinary frequency was increased by the total dose (RR=1.07) and diabetes (RR=4). Hematuria was increased by anticoagulant treatment (RR=2.9). Dysuria was increased by the total dose (RR=1.1). Corresponding nomograms and their calibration plots were generated. Nomogram performance should be validated with external data.

Conclusions:

The first nomograms to predict late urinary toxicity but also specific urinary symptoms after prostate RT were generated, contributing to prostate cancer treatment decision.

Introduction

Radical prostatectomy (RP) and radiotherapy (RT) are cornerstones of localized prostate cancer treatment, leading to relatively similar results in terms of local control [START_REF] D'amico | Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer[END_REF] . However, the side effects of both are different, mainly concerning the urinary adverse events. If the intensity of this toxicity after RT is relatively well-reported in the literature, the description of the symptoms corresponding to this toxicity is often limited. Moreover, the patient and/or treatment factors related to each of the side effects are not well known. Their identification is crucial. These factors could be used to generate urinary toxicity predictive tools (like nomograms), to guide the physician in deciding the treatment and to inform the patient, in this context of different therapeutic alternatives. To identify which radiation parameters increase toxicity is essential in understand how to decrease toxicity, in particular due to new highlyconformal radiotherapy techniques, such as Intensity Modulated Radiation Therapy (IMRT) and Image Guided Radiation Therapy (IGRT).

These new techniques allow for an increase of the dose in the prostate considering the strong dose-effect relationship for local control [START_REF] Cheung | Dose-response characteristics of low-and intermediate-risk prostate cancer treated with external beam radiotherapy[END_REF] , while limiting the dose in the bladder and the rectum. Their part in decreasing urinary toxicity has not, however, been clearly shown. If the relationship between dose-volume and toxicity has been consistently demonstrated for the rectum, it remains unclear for the bladder [START_REF] Fiorino | Dose-volume effects for normal tissues in external radiotherapy: pelvis[END_REF][START_REF] Budaus | Functional outcomes and complications following radiation therapy for prostate cancer: a critical analysis of the literature[END_REF] .

Moreover, hypofractionated RT may be more efficient in eradicating prostate adenocarcinoma, but the impact of such modified fractionation on toxicity has not been well-established.

If nomograms have already been published to predict rectal bleeding and the risk of fecal incontinence [START_REF] Valdagni | Is it time to tailor the prediction of radio-induced toxicity in prostate cancer patients? Building the first set of nomograms for late rectal syndrome[END_REF][START_REF] Valdagni | Predictive models of toxicity with external radiotherapy for prostate cancer: clinical issues[END_REF] , to our knowledge no tools have as yet been developed to = predict urinary toxicity.

We thus analyzed a large group of patients having received prostate cancer RT using different radiation techniques, total doses and fractionations, to accurately quantify and describe late urinary toxicity, identify related risk factors and propose nomograms.

Material and methods

Patient inclusion criteria

Records from 965 patients who received definitive radiotherapy for localized prostate adenocarcinoma were analyzed. Data were prospectively collected from 470 patients treated in 17 French institutions within two randomized studies: GETUG 06 (comparing 70 Gy to 80 Gy) [START_REF] Beckendorf | 70 Gy versus 80 Gy in localized prostate cancer: 5-year results of GETUG 06 randomized trial[END_REF] and STIC-IGRT (testing IGRT) [START_REF] De Crevoisier | Image-guided Radiation Therapy (IGRT) in Prostate Cancer: Preliminary Results in Prostate Registration and Acute Toxicity of a Randomized Study[END_REF] , and retrospectively from 495 patients treated in two of them. All patients had a biopsy-proven adenocarcinoma of the prostate. Pretreatment workup included a CT scan and a bone scan.

Patient and tumor characteristics

The following data were extracted from each randomized database: age, medical and surgical history (prior abdominal surgery, prior transurethral resection of prostate, anticoagulant treatment, diabetes, hypertension, coronary insufficiency) and tumor characteristics (T stage, Gleason score, pretreatment PSA). Patients were staged by digital rectal examination according to the 1992 American Joint Committee on = Cancer staging system [START_REF] Beahrs | American Joint Committee on Cancer: Manual for Staging of Cancer[END_REF] . Patients were classified into the three prognostic risk groups defined by D'Amico 1 . Patient and tumor characteristics are presented in Table 1.

Treatment characteristics

The target volume comprised the prostate only in the low risk group (16%), the prostate and the seminal vesicles in the other risk groups. The pelvic lymph nodes were not treated in the two randomized studies, but may have been treated for high risk patients of the two institutions (not treated in the randomized study) (9%). The median total dose of the prostate was 70 Gy (ranging from 65 Gy to 80 Gy), the seminal vesicles receiving 46 Gy, and the pelvic lymph nodes also 46 Gy, if treated. Dose per fraction was 2 Gy/day, 5 fractions/week for 69% of patients, or 2.5 Gy/day, 4 fractions/week for 31% of patients.

The radiation technique was 3D conformational for the vast majority of patients (85%) and 2D for 15% of the patients, depending on the treatment period. Intensity Modulated RT (IMRT) and Image Guided RT (IGRT) have been more recently used in patients receiving 80 Gy. Among the 41% of the patients having received 80 Gy, the technique was a standard 3D conformal RT for 63%, IMRT only for 18% and IMRT combined with IGRT in 19%.

The 3D radiation technique was carried out following the French GETUG group recommendations, as previously reported [START_REF] Beckendorf | 70 Gy versus 80 Gy in localized prostate cancer: 5-year results of GETUG 06 randomized trial[END_REF] . Patients underwent simulation and treatment in the supine position. Target volume and organs at risk (bladder, rectum and femoral heads) were delineated on CT slices. A bladder wall was generated with a thickness of 7 mm from the external manually-delineated bladder contour according = GETUG recommandations. The planning target volume (PTV) was calculated by adding a 10-mm margin in all directions except in the posterior where a 5-mm margin was considered. The dose-volume histogram had to respect the GETUG constraints [START_REF] Beckendorf | 70 Gy versus 80 Gy in localized prostate cancer: 5-year results of GETUG 06 randomized trial[END_REF] . The following bladder dosimetric data were analyzed: volume of the bladder wall, Dmax (maximal dose received in the bladder), D25 (minimal dose received in 25% of the bladder wall) and D50 (minimal dose received in 50% of the bladder wall).

Androgen deprivation therapy was given to 23% of the patients, all presenting a high risk cancer.

Details of treatment characteristics are presented in Table 1.

Follow up and toxicity grading

According to the protocol of surveillance, patients were evaluated every three months for a year and every 6 months thereafter Late urinary toxicity was defined as events occurring more than six months after the beginning of RT. To determine the severity and incidence of main late urinary complaints, records were prospectively extracted from trials database or retrospectively from physicians' reports, at each follow-up visit. Urinary complaints were classified according to the LENTSOMA morbidity scoring system into four categories of symptoms: urinary frequency, dysuria, incontinence and hematuria (Table 2). Dysuria and decreased stream were considered as a single symptom. The analyses were performed for late urinary toxicity and for each of the symptoms, all being considered if ! grade 2.

Statistical analysis

=

The impact of the following parameters on late urinary toxicity (! grade 2) was tested at the 5-years mark:

-Patient parameters: age, diabetes (types 1 and 2), anticoagulant treatment The data-recording modality (prospective versus retrospective collection) was verified as having no significant impact on the risk of toxicity.

The Kaplan-Meier method was used to calculate cumulative incidences of late urinary toxicity events (! grade 2). The differences between the survival curves were assessed using the log-rank test. Relationships between late urinary toxicity and patient, tumor or treatment parameters were first analyzed using Cox proportional hazard regression at univariate level. Multivariate analyses, including covariates statistically significant in univariate analysis, were carried out using the Cox proportional hazards model. The 5-year late urinary toxicity events were analyzed using logistic regression at univariate and multivariate levels. A p-value " 0.05 was considered statistically significant. Nomograms to predict 5-year late urinary toxicity and specific symptoms were built up according to the logistic model. To assess nomogram performance, a nonparametric fit of the predicted probability as regards the actual observed probability was made for each nomogram. The analyses were performed using the SPSS V18 (Chicago, IL) and = R with the rms package. Non-parametric tests were used to compare the distribution of the parameters between different groups of treatment.

Results

The median follow-up was 61 months (range 6-206).

Late urinary toxicity: global quantification and symptom description

Among the 965 patients, 183 events of late urinary toxicity grade 2 or greater were reported. Among them, only 14 % were toxicity grade 3 or 4. Ninety-two (50%) corresponded to an increase in urinary frequency, 36 (20%) to dysuria, and 48 (26%) to hematuria. Only seven consisted of urinary incontinence grade 2 or greater. The 5year and 10-year rates of grade 2 or higher urinary toxicity, urinary frequency, hematuria, dysuria and urinary incontinence were: 15% (95%CI:12%-18%) and 24% (95%CI:19%-29%), 10% (95%CI: 8%-12%) and 15% (95%CI:11%-19%), 5% (95% CI: 4-6%) and 8% (95%CI:5%-11%), 3% (95%CI: 2%-4%) and 8% (95%CI:4%-12%), and 1% (95%CI: 0%-2%) and 2% (95%CI:0%-4%), respectively. Figure 1 presents cumulative incidence of global late urinary toxicity and the corresponding symptoms (! grade 2).The 5 and 10-year rates of grade 3 or higher global urinary toxicity were 3% (95%CI: 2%-4%) and 7% (95%CI:5%-9%).

Nomograms to predict five-year late toxicity

In multivariate analysis, the following pre-planning parameters significantly positive = associated to the 5-year risk of urinary toxicity: anticoagulant treatment (RR=2.35), total dose (RR=1.09), age (RR=1.06), D25 (RR=1.03), and Dmax (RR=1.1) received by the bladder (Table 3). Nomogram including pre-treament factors to predict 5-year risk of global late urinary toxicity (and its calibration plot) is presented in Figure 2.

The 5-year risk of urinary frequency was related to total dose (RR=1.07) and diabetes (RR=4). For dysuria, the total dose was the only significant factor (RR=1.1) (Table 3). Figures 3 and4 present nomograms to predict the 5-year risk of these urinary symptoms. The 5-year risk of hematuria was significantly increased by anticoagulant treatment (RR = 2.9)

Discussion

We showed that the incidence of late urinary toxicity symptoms continuously increases after RT, reaching a rate of 24% and 7% at 10 years, for more than grade 2 and grade 3 urinary toxicity, respectively. These rates appear relatively similar to those previously observed after RT [START_REF] Beckendorf | 70 Gy versus 80 Gy in localized prostate cancer: 5-year results of GETUG 06 randomized trial[END_REF] . Urinary toxicity events may occur late after RT, later than those observed for late gastro-intestinal toxicity which generally reaches a plateau at three years after RT [START_REF] Gardner | Late normal tissue sequelae in the second decade after high dose radiation therapy with combined photons and conformal protons for locally advanced prostate cancer[END_REF] . A longer follow-up is consequently required to properly estimate late urinary toxicity [START_REF] Gardner | Late normal tissue sequelae in the second decade after high dose radiation therapy with combined photons and conformal protons for locally advanced prostate cancer[END_REF] . Comparing the risk of urinary toxicity after different treatments should therefore carefully consider the same follow-up. Late urinary toxicity symptoms are mainly characterized by urinary frequency (50% of all events) and, to a lesser extent, by dysuria and hematuria. Incontinence is very rare (<2% at 10 years).

We identified age, diabetes and anticoagulant treatment as factors increasing the risk of late urinary toxicity by multivariate analysis. Diabetes has already been reported as a strong predictor of late urinary toxicity in prostate cancer radiotherapy [START_REF] Herold | Diabetes mellitus: a predictor for late radiation morbidity[END_REF] . The = fact that anticoagulation or antiplatelet agents increase the risk of late urinary toxicity after prostate cancer radiotherapy has rarely been reported, even if this association concerns the risk of late rectal toxicity [START_REF] Takeda | Clinical correlations between treatment with anticoagulants/antiaggregants and late rectal toxicity after radiotherapy for prostate cancer[END_REF]13 . However, anticoagulation has been already associated with gross hematuria in the whole population and could be an independent risk factor of urinary complaints whatever a radiation is performed. Age and diabetes have been previously associated with urinary side effects after radical prostatectomy, especially urinary incontinence 14,15 . Thus, their implications in urinary toxicity after RT should not be underestimated in treatment decision.

We found a strong dose-effect relationship in urinary toxicity (global toxicity, urinary frequency and dysuria). Most of the randomized studies comparing a "standard" dose (68 to 70 Gy) to a higher one (76 to 80 Gy) did not demonstrate such a significant increase in late urinary toxicity [16][17][18][19] . However, in a large group of patients who received a dose escalation with 3D-CRT/IMRT, Zelefsky et al reported a significant increase of genitourinary (GU) toxicities after 10 years in patients who received higher doses 20 . More recently, the GETUG 06 randomized trial reported such an increase, when escalating the dose from 70 Gy to 80 Gy 7 . These differences can be explained by several reasons. The first one is the lack of follow-up. Indeed, the initial MDACC report that compared 78Gy to 70Gy did not show a significant difference in late GI toxicity, while it was found with a longer follow-up 16 . Secondly, studies might be different in terms of their treatment scheme (dose, target volume, technique), patient characteristics and grading scale. Finally, urinary toxicity might be more related to patient risk factors than dose parameters. The lack of correlation between dose distribution (dose-volume histogram) and urinary toxicity may also be due to the large bladder volume variation occurring at the planning stage and at the different = fractions, so that the planned dose distribution does not represent the actual delivered dose to the bladder.

A moderate hypofractionned schedule (2.5 Gy/fr) in our series did not increase late urinary toxicity. These results are concordant with contemporary studies 21 and emphasize the interest of hypofractionated schedule in prostate cancer radiotherapy.

IMRT and IGRT aim at increasing local control by allowing dose escalation, while reducing toxicity by sparing normal surrounding tissues. Compared to "standard" 3D conformal technique, IMRT clearly reduces the risk of long-term rectal toxicity and bowel dysfunction 20,22,23 . However, IMRT fails to decrease late urinary toxicity in most studies, as in the present one. Late urinary toxicity could even be partly due to prostatic urethra lesions [START_REF] Wallner | Dosimetry guidelines to minimize urethral and rectal morbidity following transperineal I-125 prostate brachytherapy[END_REF] , and modern techniques such as IMRT combined with IGRT still do not allow for the preservation of this area. A recent non-randomized study of Zelefsky et al reported however that, with a median follow-up of 2.8 years and a high dose (86.4 Gy) delivered to the prostate by IMRT, patients treated with IGRT (using fiducials) experienced significantly less urinary toxicity than non-IGRT treated patients [START_REF] Zelefsky | Improved Clinical Outcomes with High-Dose Image Guided Radiotherapy Compared with Non-IGRT for the Treatment of Clinically Localized Prostate Cancer[END_REF] .

Based on this predictive factors, we propose the first nomograms to predict late urinary toxicity after radiation therapy. Indeed, many treatments now provide long term survival and the decision of the patient concerning his own treatment is mainly based on expected side effects. These nomograms have been built up according to the pre-treatment parameters, available before any CT simulation, in order to help physician and patient in the decision concerning the different prostate cancer treatments. Consequently, we believe that the corresponding nomograms concerning toxicity after radical prostatectomy should be proposed.

One limitation of our study is that both prospective and retrospective data (from 2 = institutions) were used to assess our nomograms. However, the effect of data being retrospectively collected was not found to significantly impact on toxicity risk. Furthermore, a large number of patients was necessary to identify a maximum number of reliable toxicity predictors. Finally, nomogram performance has been validated within our series but should be also confirmed using external data.

Conclusions

We were able to identify several parameters increasing the risk of urinary toxicity after prostate cancer radiotherapy. The first nomograms to predict global late urinary toxicity and corresponding symptoms were generated, resulting in new tools for patient management and treatment decision, particularly between RT and surgery.

(

  vitamin K antagonist or antiplatelet drug), prior abdominal or pelvic surgery, prior transurethral resection of prostate, hypertension, coronary insufficiency; -Tumor parameters: Gleason Score, T stage, prognostic group (D'amico); -Treatment parameters: RT technique (2D technique, 3DConformational technique, with or without IMRT/IGRT), total dose and fractionation, target volume, dosimetric bladder parameters (volume of the bladder wall, maximal dose, D25, D50) and androgen deprivation.

Figure legends Figure1:Figure 2 :

 legends2 Figure legends

Figure 3 :Figure 4 :

 34 Figure 3: Five-year risk of urinary frequency grade ! 2: nomogram and

Table 1 : Patient, tumor and treatment characteristics 435

 1

		Patient characteristics
	Number of patients		965
	Mean age,.yr (range)		68 (45-83)
	Diabetes*			7%
	Anticoagulant treatment**		21%
	Prior abdominal or pelvic surgery		34%
	Prior transuretral resection of prostate		6%
	Hypertension			19%
	Coronary insufficiency		9%
		Tumor characteristics
	PSA, ng/ml (range)		15 (0-133)
			<7	53%
	Gleason Score		7	38%
			>7	9%
			T1	25%
	T stage		T2	62%
			T3	13%
	Prognostic group of risk (D'amico) :	Low Intermediate High	18% 51% 31%
		Treatment characteristics
		Radiotherapy technique
	2D Technique			15%
	« Standard » 3D Conformational (without IMRT)		66%
	IMRT (without IGRT)		7%
	IGRT (with IMRT)		12%
		Prescribed dose and fractionation
	65 Gy	2.5Gy. 4/w		15%
	70 Gy	2.5Gy. 4/w 2Gy. 5/w		16% 28%
	80Gy	2Gy. 5/w		41%
		Target volume
	Prostate only			16%
	Prostate + Seminal vesicles		75%
	Prostate + Seminal vesicles + Pelvic lymph nodes		9%

Table 2 : LENTSOMA grading scale (Urinary symptoms)

 2

		grade I	grade II	grade III	grade IV
	Subjective
	Dysuria	occasional and minimal	intermittent and tolerable	persistent and intense	refractory and
					excruciating
	Decreased	occasionally weak	intermittent	persistent but incomplete	complete obstruction
	stream			obstruction
	Frequency	3-4-h intervals (6-8/day)	2-3-h intervals (9-12/day) 1-2-h intervals (13-24/day)	hourly (>24/day)
	Hematuria	occasional	intermittent	persistent with clot	refractory
	Incontinence	< weekly episodes	< daily episodes	pads/undergarments/day	refractory
	Management
	Dysuria	occasional, nonnarcotic	regular nonnarcotic	regular narcotic	surgical intervention
	Decreased		< 1/day self catheterization dilatation or TUR, > 1/day self	permanent catheter,
	stream			catheterization	surgical intervention
	Frequency		occasional antispasmodic	regular narcotic	cystectomy
	Hematuria	alkalization iron therapy	single transfusion or	frequent transfusions or	surgical intervention
			cauterization	coagulations
	Incontinence	occasional use of	intermittent use of	regular use of incontinence	catheterization
		incontinence pads	incontinence pads	pads or self	permanent catheter