Usage of di ﬀ erent vessel models in a ﬂ ow-through cell: in vitro study of a novel coated balloon catheter

Drug-coated balloon catheters are a novel clinical treatment alternative for coronary and peripheral artery diseases. Calcium alginate, poly(vinylethylimidazolium bromide) and polyacrylamide hydrogels were used as vessel models in this in vitro study. In comparison to a simple silicone tube their properties can be easily modi ﬁ ed simulating di ﬀ erent types of tissue. Local drug delivery after balloon dilation in the ﬁ rst crucial minute was determined in a vessel-simulating ﬂ ow-through cell by a simulated blood stream. Balloon catheters were coated with paclitaxel using the ionic liquid cetylpyridinium salicylate as a novel carrier. Drug transfer from coated balloon catheters to di ﬀ erent simulated vessel walls was evaluated and compared to a silicone tube. The highest paclitaxel delivery upon dilation was achieved with calcium alginate as the vessel model (60%) compared to polyacrylamide with 20% drug transfer. The silicone tube showed the least amount of wash-o ﬀ (<1%) by a simulated blood stream after one minute from the vessel wall. The vessel-simulating ﬂ ow-through cell was combined with a model coronary artery pathway to estimate drug loss during simulated use in an in vitro model. Calcium alginate and polyacrylamide hydrogels were used as tissue models for the simulated anatomic implantation process. In both cases, similar transfer rates for paclitaxel upon dilation were detected.


Introduction
Drug-coated balloon (DCB) technologies have emerged as a potential alternative to drug eluting stents (DES) to minimize restenosis. 1 The applied drug should exhibit specic chemical properties and mechanism of action as well as pharmacokinetics and a fast transfer to be quickly absorbed by the vessel wall. 2 Paclitaxel (PTX), a cytotoxic agent, was determined as the primary drug for DCB due to its efficient uptake as well as its extended retention. 3The cytotoxic, anti-proliferative effect of DES on the vessel wall has been widely explored. 2,4Preclinical studies with DCB have shown that 3 mg mm À2 paclitaxel is the effective dose to achieve an efficient, long-term, antiproliferative effect on the vessel wall. 2,5Drug delivery during angioplasty depends on drug dose, transfer system, dilation time, release pattern and appropriate balloon coating.][8] In addition to pure PTX balloon catheters different PTX formulations with additives such as urea, butyryl-tri-hexyl citrate (BTHC), iopromide and Shellac (aleuritic and shellolic acid) are commercially available. 6Kleber et al. summarized clinical evidence for these different DCBs in coronaries arteries with CE-mark (Conformité Européene). 7he Paccocath technology with PTX embedded in hydrophilic iopromide coating increases the solubility and thus the transfer of PTX to the vessel wall.More than 80% of the drug is retained during balloon implantation to the target tissue (lesion) and 10-15% of the drug is released in the vessel wall upon 60 s balloon ination. 3FreePac technology uses the natural additive urea as a carrier, which should enhance drug release as well as absorption, and thereby reduce total drug elution times (30-60 s).During balloon ination, the blood ow in the vessel is interrupted and therefore expansion can only be maintained up to one minute.Microporous balloon surfaces with Shellac coating technology can be inated up to one minute and achieve total drug release.A shorter dilation time results in partial drug release. 2,3In a porcine model vessel wall, Scheller et al. have demonstrated a drug release of approx.90% aer one minute ination and 40 to 60 minutes later, they could detect about 10% PTX in the vessel wall.Thus, PTX is transferred into and retained by the pig tissue for a certain time. 91][12] The previously used models are far from physiological properties of the material, e.g. a silicone tube acts like an artery.We have been working on polymerized ionic liquids (PILs) which are able to form hydrogels.Depending on the type of ionic liquid and degree of cross-linking the mechanical properties can be modied. 13In our presented study, these hydrogels were evaluated to act as vessel model and compared to known hydrogels.Next to calcium alginate as a natural hydrogel, synthetic polymers with good mechanical and long-term stability were also used. 13PTX-coated balloon catheters using the ionic liquid cetylpyridinium salicylate (Cetpyrsal) as a novel innovative additive were studied. 11Local drug delivery within a vesselsimulating ow-through cell under physiological conditions during the rst crucial minute was investigated.For an assessment of this study, the total drug delivery upon dilation (retention into the hydrogel and wash-off (release) from the hydrogel compartment by a simulated blood stream) and the residual load on the balloon were analyzed.Furthermore, the drug loss during a simulated insertion was estimated by combining the ow-through cell with a model coronary artery pathway.

Balloon coating
A pipetting technique was used for the coating of the inated balloon catheter according to Petersen et al. 11 Briey, PTX and Cetpyrsal were separately dissolved in methanol to yield concentrations of 4.72 mg mL À1 (both stock solutions).Following this, a Cetpyrsal-PTX solution (50%, w/w) was mixed from both stock solutions.100 mL of the Cetpyrsal-PTX solution was then slowly pipetted onto each balloon catheter, resulting in a PTX surface load of approx.3 mg mm À2 , respectively a total of 659.73 mg (balloon 1: 3.5 mm diameter, 20 mm length), 753.99 mg (balloon 2: 4.0 mm diameter, 20 mm length) or 1130.97 mg (balloon 3: 4.0 mm diameter, 30 mm length).During the pipetting process, the balloon was rotated and evaporation of methanol was ensured by a gentle stream of air.Finally, all balloon catheters were dried at 23 AE 2 C overnight. 11ed balloons during in vitro study.Silicone tube (only balloon type 2), calcium alginate (trial 1: balloon 2, trial 2-6: balloon type 1), poly(VEImBr) hydrogel (only balloon type 2), PAAm (trial 1-3: balloon type 2, trial 4-6: balloon type 3).For the model ASTM F2394-07 only balloon type 2 was used.

Hydrogel preparation
Calcium alginate hydrogel.Sodium alginate (3%, w/w) was dissolved in de-ionized water.To 0.15 g CaSO 4 $2H 2 O 1500 mL de-ionized water was added and to the resulting suspension, 500 mL of a 10% (w) Na 3 PO 4 $12H 2 O solution was added.16.5 g alginate sol (3%, w/w) was mixed by a sheet of strong paper with this fresh calcium-containing suspension and was lled in the vessel-simulating ow-through cell.Aer complete gelation, the metal rod was removed from the ow-through cell and a simulated articial vessel wall was obtained.
Polyacrylamide (PAAm) hydrogel.PAAm was synthesized by radical polymerization.Rotiphorese® Gel 30 (3.975 mL) was added to 10.794 mL de-ionized water.Polymerization was initiated by adding 210 mL fresh APS solution (10%, w/w) and TEMED (21 mL).Aer a short reaction time (2-3 min), the owthrough cell containing the metal rod was lled with the polymerizing solution.Following full gelation, the metal rod was removed from the system Poly(vinylethylimidazolium bromide) hydrogel (poly-(VEImBr)).7.5 g of 1-vinyl-3-ethyl-imidazolium bromide (36.93 mmol, [VEIm][Br]), synthesis previously described by Bandomir et al., was dissolved in 11.675 mL de-ionized water. 13otiphorese® Gel B (4.925 mL), 750 mL APS solution (10%, w/w) and 150 mL of TEMED were added.The solution was mixed using a Vortex and aer a short reaction time (1-2 min), the ow-through cell containing the metal rod was lled with the polymerizing solution. 13The metal rod was removed following complete hardening of the hydrogel.

Simulated use of DCB in a ow-through cell in different vessel models
An adapted vessel-simulating ow-through cell was chosen, which is described in detail by Seidlitz et al. 15 Instead of the acrylic glass disc a metal disc was used.Calcium alginate, PAAm and poly(VEImBr) hydrogels were inserted as hydrogel compartments.The DCB was placed in the simulated vessel wall and dilated for 60 s with a nominal pressure of 7 bar.The owthrough cell with the inated balloon catheter is shown in Fig. 1 with PAAm hydrogel as the vessel model.Aer expansion, the balloon was removed and isotonic sodium chloride (NaCl, 0.9%) as a perfusion medium was circulated along the simulated vessel wall for a duration of 1 min at a ow rate of 35 mL min À1 .Pumping of medium was managed with a gear pump (Ismatec MCP-Z ISM 405A, pump head model 186-000, Germany; Tygon® tube R 3607, 3.17 mm ID, VWR International GmbH, Germany) and the set ow rate was adjusted to the blood ow velocity in coronaries. 16The isotonic solution was collected in a falcon vessel and the PTX concentrations were measured by HPLC (see HPLC parameters).The process of balloon angioplasty was simulated applying an in vitro model, consisting of a guiding catheter (Cordis® Vista Brite Tip®; 6F; 1.75 mm ID; 90 cm) with a guide wire (Biotronik SE & Co KG, Galeo M 014) and a ow-through cell with different hydrogel compartments at the end of the test path, representing the vessel wall.Experiments were also performed with a silicone tube (3.0 mm ID) as the vessel model to compare the results.Paclitaxel transfer into different simulated vessel walls was measured.Before balloon dilation, the guiding catheter and vessel model were ushed with 20 mL NaCl-solution (0.9%).PTX-coated balloon catheters using Cetpyrsal additive were inserted into the guiding catheter and via a guide wire, the balloon catheter was placed in the simulated vessel wall.
Aer balloon deation, the pump was started (ow rate 35 mL min À1 ).The PTX concentration simulating drug wash-off from the vessel model within the rst crucial minute was determined by HPLC measurements.The guiding catheter was then ushed with 20 mL methanol.The balloon catheter was extracted in 10 mL methanol for 30 min at 23 AE 2 C and then the residue on the balloon was analyzed.The used hydrogel aer cutting into small pieces was also extracted with methanol (20 mL) for 30 min at 23 AE 2 C to detect the amount of transferred drug into the vessel model.The entire guiding catheter was then ushed with 20 mL of 0.9% NaCl-solution in preparation of the next experiment.In summary, the total PTX delivery upon dilation composed of drug transfer into the hydrogel and drug wash-off from the hydrogel compartment aer 1 min by a simulated blood stream.All samples were quantied by means of HPLC aer a 1 : 2 dilution with methanol.

Simulated use of DCB in the vessel-simulating owthrough cell aer passage through an in vitro vessel model according to ASTM F2394-07
A standard anatomic model adapted from ASTM F2394-07, recently described in the literature as a standard procedure, was applied to simulate the implantation process of DCB. 17 The model consisted of polymethacrylate plates forming a simulated course of a coronary artery.The used guiding catheter (Cordis® Vista Brite Tip®; 6F; 1.75 mm ID; 90 cm) with a guide wire (Biotronik SE & Co KG, Galeo M 014) and the tortuous path equipped with a PTFE tube was placed in a 37 AE 2 C heated water bath (Fig. 2).The model was ushed with 30 mL 0.9% NaCl-solution.A DCB was introduced into the guiding catheter of the model and initially placed at the end of the PTFE tube.The guiding catheter was then ushed with 30 mL 0.9% NaClsolution to recover particles and PTX released during tracking.At the distal end of the test path, a hydrogel vessel model (calcium alginate or PAAm) was placed and the balloon was dilated to 7 bar and held for 1 min.The balloon was removed aer deation and extracted in 20 mL methanol for 10 min (residual PTX load on the balloon) at 23 AE 2 C. The pump was then started (ow rate 35 mL min À1 ) and the PTX concentration simulating the drug wash-off in the rst crucial minute was determined.Then the used hydrogel aer cutting was also extracted with methanol (20 mL) for 30 min at 23 AE 2 C (drug transfer into the vessel model).Aer balloon extraction (10 min) in methanol, the balloon was removed and the entire pathway was then nally ushed with 30 mL methanol.Subsequently, the test path was ushed with 0.9% NaCl-solution in preparation of the next balloon dilation.
The total PTX delivery upon dilation composed of drug transfer into the vessel model (hydrogel) and drug wash-off from the hydrogel compartment aer 1 min by a simulated blood stream.All samples were quantied by means of HPLC aer a 1 : 2 dilution with methanol.

Comparison of different hydrogels in the ow-through cell
The rst set of experiments of DCB compared different hydrogels as tissue models to evaluate drug release of PTX.Drug  transfer, the retention of PTX into three different hydrogels as tissue models respectively vessel walls as well as the wash-off (release) from the hydrogel compartment within a vesselsimulating ow-through cell were investigated during balloon dilation.A PTX transfer should be examined by using different hydrogel compartments to determine the inuence of the tissue model relating to the PTX transfer upon dilation.Certain properties of the used hydrogels to simulate a vessel wall such as permeability, exibility and long-term stability of synthetic polymers (poly(VEImBr) and PAAm) are of particular importance.Calcium alginate as a natural polymer is easily accessible but has limited long-term stability.Monovalent cations such as Na + dissolve the network within short time.In addition, alginate hydrogels are prone to microbial contamination.Results for various vessel models are depicted in Fig. 3.The total PTX delivery upon dilation composed of drug transfer into the hydrogel and drug wash-off from the hydrogel compartment aer 1 min by a simulated blood stream.In the following the results from the balloon dilations will be discussed.
Drug transfer into the vessel model (Fig. 3, entry 1).The PTX transfer into the vessel models are listed in Table 1.Drug delivered in the silicone tube was extracted with methanol (38.6 AE 3.4%, 1.02 AE 0.03 mg mm À2 ).Considerably lower PTX was delivered into hydrogel-based vessel models.In the case of calcium alginate as the vessel wall, a PTX content in the hydrogel of 21.4 AE 10.7% (0.53 AE 0.23 mg mm À2 ) was detected.Alternatively, with PAAm as the vessel wall, only 2.8 AE 1.8% (<0.1 mg mm À2 ) of PTX was transferred into the hydrogel.There are different possibilities for interpretation of the observed results.Drug transfer from coated balloons to the simulated vessel wall could occur in different ways.Paclitaxel may dissolve on contact with the hydrogel compartment and diffuse into the gel.Thus, solubility is very important for drug release and delivery.Dissolution depends on solubility of the used drug in 0.9% NaCl-solution.Liggins et al. published a maximum solubility of anhydrous PTX of 3.59 AE 0.41 mg mL À1 in water aer 3 h at 37 C. 18 Another report described a solubility of <0.1 mg mL À1 in aqueous medium, which is quite low. 19Water solubility could be increased by synthesis of derivatives, under the risk of changing pharmaceutical characteristics. 20Due to very poor solubility of PTX in water, transport via dissolution and diffusion into the hydrogel is not responsible for the main transfer.Another drug transfer pathway may occur by particle transfer of PTX due to prevailing mechanical forces during balloon expansion onto the vessel wall.Over a period of one minute, a contact between the expanded balloon and simulated vessel wall is established, thus allowing transfer of PTX particles.The contact time was consistent in every case, but the inner diameter of the silicone tube (3.0 mm) was different in comparison to the articial vessel walls (3.14 mm).Hence, the prevailing mechanical forces during balloon expansion in the silicone tube were stronger and more PTX could be transferred.To conclude, the main PTX transfer during balloon expansion occurred due to prevailing mechanical forces.
Furthermore, the hydrogel characteristics were important for PTX transfer and diffusion into hydrogels. 21PAAm and poly-(VEImBr) were synthetic polymers with a specic cross-linker content (poly(VEImBr): 1.7% to PAAm: 0.8% cross-linker content). 13On the contrary, the calcium alginate hydrogel is a natural polymer with variability in its properties.In addition to mechanical properties (exibility) of the vessel models, different adhesion properties were present.This corresponds to different amounts of PTX wash-off from the vessel models aer 1 min by a simulated blood stream (see Table 1 or Fig. 3).Moreover, the diffusion of PTX into the vessel wall occurs at various rates, which may be related with the cross-linker content.This leads to PTX diffusion into synthetic polymers < 5% (poly(VEImBr) and PAAm) compared to the natural polymer of 21.4 AE 10.7%.
Drug wash-off from various vessel models aer 1 min (Fig. 3, entry 2).A drug release time of only one minute was chosen to simulate a very fast PTX transfer and wash-off from the vessel model.The silicone tube is a hydrophobic material and showed the least amount of wash-off (<1%) from the vessel model (see Table 1).Silicone tubes as a vessel model were not very suitable because they are not similar to physiological uptake behavior.A hydrogel is a network of polymer chains that are hydrophilic and should be more appropriate. 22,23With a hydrogel compartment as a vessel wall, the PAAm was able to achieve the lowest wash-off quantities (17.8 AE 5.3%, 0.40 AE 0.14 mg mm À2 ), compared to poly(VEImBr) (28.7 AE 26.2%) and calcium alginate  (41.2 AE 14.2%, 1.15 AE 0.58 mg mm À2 ).Thus, the highest drug wash-off aer 1 min was achieved in case of calcium alginate as the vessel model.The simulated vessel models chosen were important for an effective drug transfer.Thus, the drug delivery characteristic is dependent on the hydrogel compartment.With poly(VEImBr) as the hydrogel compartment, some analytical problems occurred.Thus, their potential could not be fully explored.The poly(VEImBr) hydrogel shows strong swelling behavior in methanol which was used to extract the drug from the hydrogel.Most of the solvent diffused into the polymer and thus the hydrogel rapidly swells.In addition, the high salinity compromised the HPLC analysis of PTX (value for drug washoff, see Table 1) and therefore elongated peaks in the chromatogram were difficult to integrate together with a low interpretable reproducibility of the data.This could be overcome by using other drug candidates or models showing, for example, uorescence.In summary, the hydrogel material was crucial for the total drug delivery upon dilation (Fig. 3).Since the drug is poorly soluble in water and because of binding to tissue structures, the PTX may persist longer in the vessel wall.Calculated curves for PTX tissue concentration as function of time are provided in the literature.Within the rst hour, the concentration decreases dramatically. 24rug residue on the balloon.The residual loads of PTX on the balloon catheter were also determined (Fig. 3, entry 4).Extraction of the balloon in methanol resulted in the highest PTX concentration for the silicone tube (59.5 AE 4.6%, 1.6 AE 0.2 mg mm À2 ) as the vessel model, meaning most of the PTX remained on the balloon surface.Only 40% of the drug could be transferred during balloon dilation.However, considerably less drug on the balloon catheter surface were analyzed in the cases of dilation in calcium alginate (30.8 AE 7.6%, 0.8 AE 0.2 mg mm À2 ) and PAAm (33.2 AE 15.3%, 0.8 AE 0.4 mg mm À2 ) as vessel models.Consequently, in both cases about 70% of the drug is removed from the balloon catheter.
As already mentioned, PTX is characterized by its very low solubility.The balloon catheters used here exhibit homogeneous coating due to the use of an IL as a novel additive (Cetpyrsal/PTX, 50/50, w/w).There are no needle-like crystals present on the balloon surface. 11Previous experiments showed that the novel additive reduced the drug loss compared to a commercially available DCB with an urea-based coating. 11For this reason, there is the possibility to deliver (transfer) more PTX during the balloon expansion and therefore we concentrated on this novel DCB.The degree of crystallization is important; Afari et al. published that more crystalline coatings yield higher tissue levels and biological efficacy. 25In contrast, less crystalline coatings resulted in improved uniformity and less particle formation. 25Heilmann et al. had found (via an in vivo study) that the advantageous effect of a hydrophilic additive such as using iopromide for higher tissue concentrations was antagonized by increased amounts of wash-off of used coatings. 26rug loss is a process constituted of mechanical loss by sheath passage and collisions with the vessel wall and dissolution of the coating in the blood stream. 26This process will be simulated using a standard anatomic model adapted from ASTM F2394-07 (described in next section).Drug adherence and loss on the way to the vessel was tested in vitro by Kelsch et al. 8 Drug loss upon passage through a blood-lled hemostatic valve and guiding catheter for one minute in stirred blood at 37 C was investigated.Urea-based DCB lost 26 AE 3% and iopromidebased DCB lost 36 AE 11% of the total amount on the balloon. 8n conclusion for the simulated use of DCB, the total drug delivery upon dilation is different for the used hydrogels simulating the vessel wall.Calcium alginate hydrogel as the vessel model showed the highest PTX delivery upon dilation.The wash-off from the alginate hydrogel was high (drug release aer 1 min by a simulated blood stream: 41.2 AE 14.2%).However, 21.4 AE 10.7% of the drug diffused into the hydrogel compartment.The silicone tube showed the least amount of wash-off (<1%) from the vessel model aer 1 min, but it is quite different to natural vessels.Poly(VEImBr) hydrogels as vessel models were difficult to analyze.In the case of PAAm as the vessel model, only 20% of PTX could be delivered upon dilation.

Simulated use of DCB in the vessel-simulating owthrough cell aer passage through an in vitro vessel model according to ASTM F2394-07
In order to simulate the implantation process, the vesselsimulating ow-through cell was combined with a model coronary artery pathway to estimate drug loss and transfer as well as particle release.Cetpyrsal-based DCBs were manually advanced through a tortuous vessel path, consisting of a guiding catheter with a guide wire.Calcium alginate and polyacrylamide hydrogels were used as tissue models for the simulated use in an in vitro model (Fig. 4).The obtained results can be compared with the data from Petersen et al. 11 In their study, they also used the anatomic model according to ASTM F2394-07 with a silicone tube as the vessel model.
Total PTX delivery upon dilation (Fig. 4, entry 1).Only small transferred fractions were observed for both vessel models aer passage of the balloon catheter through a simulated anatomic model.In the case of PAAm, a total PTX delivery upon dilation of 5.1 AE 2.1% (0.14 AE 0.06 mg mm À2 ) was achieved.Similar transfer rates for PTX upon dilation were detected with calcium alginate as the vessel model (6.4 AE 3.8%, 0.13 AE 0.07 mg mm À2 ).As before, a short wash-off time (drug release aer one minute) was chosen to simulate the drug behavior aer pass through the tracking model.With PAAm as the vessel model, a PTX content of 1.7 AE 0.7% could be detected in the wash-off solution.A similar value for calcium alginate as the vessel model was found (PTX content of 2.0 AE 1.1%) as wash-off from the hydrogel compartment in the rst minute.The PTX transfer into the hydrogel compartment was slightly higher (PAAm: of 3.4 AE 1.9%; calcium alginate: of 4.3 AE 2.8%).Thus, the drug diffused into the vessel model or adhered on the vessel wall and was not released in one minute into the medium.However, the total PTX delivery upon dilation was similar for two different vessel models aer the simulated implantation process.Petersen et al. transferred more PTX in the silicone tube (up to 40%) with a PTX-Cetpyrsal balloon catheter (50 : 50, w/w) coated in a folded condition.With the balloon coated in an expanded condition, the PTX transfer in the silicone tube was lower (5-15%). 11Here, the used balloon catheters were coated in an expanded condi-Seidlitz et al. used pure PTX-coated balloons and showed PTX transfer rates to gel below 1% (calcium alginate as vessel model). 12In their study, they also used a model of a coronary artery pathway to investigate drug loss and drug transfer to the gel.However, in our study with the novel DCB coating more PTX was delivered upon dilation (calcium alginate: 6.4 AE 3.8% compared to below 1%).In conclusion, the PTX transfer upon dilation depends on the coating of the balloon and the used vessel model simulating the vessel wall.
Drug residue on the balloon (Fig. 4, entry 2).Extraction of the balloon catheter in methanol resulted in a PTX content of 1.38 AE 0.46 mg mm À2 with PAAm as the vessel model (Fig. 4).Consequently, there was still 51.4AE 15.7% PTX remaining on the balloon surface and about 50% of the drug is removed from the balloon catheter.However, expansion of the balloon in calcium alginate yielded only 0.27 AE 0.14 mg mm À2 PTX residue on the balloon (13.3 AE 8.3%).The balloon was almost completely unloaded.
Particle quantication.In addition to the total drug delivery upon dilation, particle measurements (>10 mm, >25 mm) were performed aer track and dilation of the balloon (Table 2).These size limits (>10 mm, >25 mm) are assumed from the evaluation of surface and coating damage of stent delivery catheter.The estimated mechanism from DCB involves the delivery of particles to the inner lumen of coronary arteries, the release of particles or coating fragments in the coronary arteries.Complications are occlusions of small vessels or capillaries. 17,27Quantied particles are mainly PTX particles because Cetpyrsal does not form any ascertainable particles in aqueous solution under used conditions.
Using calcium alginate as the vessel model, a total of 589 AE 309 particles (>10 mm) per mm 2 were analyzed.Contained particles >25 mm per mm 2 were detected in a ratio of 1 : 10 (57 AE 28).In the second test series using PAAm, the expected sum of particles was decreased (234 AE 127 (>10 mm) per mm 2 , 34 AE 7 (>25 mm) per mm 2 balloon surface).Petersen et al. described that DCB based on Cetpyrsal generated a lower quantity of particles (expanded condition: 280 AE 91 particles (>10 mm) per mm 2 balloon surface) compared to commercially available DCB using a urea-based coating (329 AE 161 particles (>10 mm) per mm 2 balloon surface). 11Amounts of particles generated from the PTCA balloon catheters by comparing two modied lubricous polymeric hydrogel coatings used at various thicknesses were demonstrated by Babcock et al. 28 In their study, a submicron coating (dry thickness of 0.5 mm) generates far fewer particulates than the micron coating (dry thickness of 2 mm) on the same substrate in a standard anatomic model adapted from ASTM F2394-07. 28

Conclusions
Drug-coated balloon catheters are an alternative for coronary and peripheral artery disease.Based on the limited number of published results of in vitro characterization of drug coated balloons, there is a need for further research.Novel PTX-coated balloons using ionic liquid Cetpyrsal as an additive for the in vitro study were applied.Drug delivery upon dilation in different tissue models (calcium alginate, poly(VEImBr) and PAAm) using a vessel-simulating ow-through cell was investigated and compared to a silicone tube as the tissue model.The highest PTX delivery upon dilation was achieved with calcium alginate as the vessel model (about 60%).However, a total PTX delivery upon dilation of 20% was determined with polyacrylamide as vessel model.The used vessel models showed seemingly various adhesion properties, thus the PTX wash-off quantities during simulated blood ow were different.The silicone tube showed the lowest amount of wash-off (<1%) from the vessel model aer 1 min simulated blood stream.The highest drug wash-off (release) was achieved with calcium alginate as vessel model.Moreover, the diffusion of PTX into the vessel wall occurs at various rates, which may be related to the cross-linker content of the hydrogels.In addition to solubility and thus diffusion of PTX, the hydrogel material as well as the coating was crucial for drug transfer from the balloon into the vessel wall when compared to reported data.Furthermore, the vessel-simulating ow-through cell was combined with a model coronary artery pathway to simulate an anatomic implantation process.Vast amounts of the coated drug were lost during a simulated artery pathway.Only a small fraction of the total loads of PTX were delivered upon dilation.Similar transfer rates for PTX upon dilation were achieved with calcium alginate and PAAm as vessel models.The crucial drug delivery upon dilation was examined with the aid of different hydrogel materials to

Fig. 3
Fig.3Drug transfer rate for PTX in different in vitro vessel models.

Fig. 4
Fig. 4 Total drug transfer rate upon dilation for PTX after simulated anatomic passage.

Table 1
Total PTX delivery upon dilation in different vessel models after simulated use in an in vitro vessel model a a n.a.: not available.

Table 2
Particle quantification after simulated anatomic passage Open Access Article.Published on 09 January 2015.Downloaded on 10/22/2023 4:25:21 PM.This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.evaluate the in vitro research.These are important data for the in vivo application.