Abstract
Infusion catheters, when used with balloons, are susceptible to compression of the catheter lumen. A consequence is that shear stress is increased in the fluid that passes through the lumen. When the injected fluid contains viable cells, hemolysis of the cells can result. This study investigates the effect of a new injection catheter design which is intended to resist the deleterious effect of balloon compression on cell viability for various flowrates, balloon pressures, and fluid viscosity values. Two types of catheters were employed for the study; a standard single-lumen device and a newly designed multi-lumen alternate. Experimental and numerical simulations show that for a single-lumen injection catheter, balloon pressures in excess of 7–8 atm have the potential for causing hemolysis for flows of approximately 1–4 ml/min. The critical balloon pressure is dependent on the viscosity of the cell-carrying fluid and the injectant flowrate. Higher injection rates and viscosities lead to lower threshold balloon pressures. The results show a sharp rise in cell death when pressures rose above approximately 7 atm. On the other hand, the multi-lumen design was shown to resist hemolysis for all tested and simulated balloon pressures and flowrates up to 10 ml/min. Experimental results confirmed the numerical findings that hemolysis-causing shear stress was not found with the multi-lumen, up to 12 atm. This study indicates that a pressure-resistant multi-lumen catheter better preserves cell viability compared to the standard.
Highlights
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A catheter is described that is used to inject living therapeutic fluid.
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The investigation compares the catheter to a single-lumen device.
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The new catheter lowers shear stress and better preserves living cells.
1
Introduction
The use of catheters to deliver medication intravenously is a common practice in medical therapy. Among more novel uses is the delivery of living stem cells following myocardial infarction, heart failure or refractory angina .
For stem cell injections, a number of issues should be given special consideration. For instance, protection of the therapeutic medium (maintaining cell viability) is important. Reduction of cellular clumping and effective separation of the agent is also important. Separately, but related, is the dispersion of the therapeutic medium within the artery downstream of the injection site. Finally, preservation of the inner injection lumen(s) area is an issue when the catheter is used with an inflation balloon that results in a compressive force on the catheter.
These issues motivate the present study which will report on the flow performance of a newly designed multi-lumen catheter. Comparisons will be made between the newly designed catheter and a standard single-lumen device. The comparison will focus primarily on the ability of the two catheters to resist the compressive force of an inflation balloon and on their ability to deliver viable stem cells for various inflation pressures and therapeutic flowrates. Additionally, the ability of the catheters to disperse a therapeutic fluid downstream of the injection local will be investigated.
2
Materials and methods
By way of an overview, this study involved multiple stages and analysis tools. First, numerical simulations were carried out for the fluid flow in both catheters. The simulations provide detailed information on the flow characteristics for both devices, including pressure, shear stress, transition time, and velocity within the fluid. These data were used to determine the likelihood of mechanical hemolysis of the stem cells as they passed through the device.
Second, independent experiments were performed to characterize the catheter compression for various balloon inflation pressures and this information was used to evaluate the likelihood of cellular injury during injection. Comparisons were then made between the experimental and simulated results; it was found that there was excellent agreement.
2.1
Simulations
The simulations refer to an established flow analysis tool termed computational fluid dynamics. This analysis methodology refers to the solution of complex flow problems by subdividing the fluid region into a large multitude of regularly shaped elements (sometimes called cells or volumes). At each element, basic equations conserving mass, momentum, and species are solved. The outcome of these calculations is a continuous variation of flow parameters (such as pressure, velocity, density, stress, etc.). For the present study, the selected single-lumen catheter was a Trek Coronary Dilatation Catheter (Abbott Vascular, Santa Clara, CA). The alternative multi-lumen device is the FlowFusion™ ND® Infusion Catheter (Cook Regentec, Indianapolis, IN).
For both devices, the first stage of the simulation process was the creation of a digital representation of the physical device. For the single-lumen catheter, Fig. 1 provides a display of the digital rendition.
The catheter of Fig. 1 was then situated within an artery (3.5 mm inner diameter) and whose length was 11 cm. The solution space was extended sufficiently far upstream of the injection location so that its position did not artificially influence the results. A dimensioned image of the solution domain is provided in Fig. 2 . The large length-to-diameter ratio of the artery and device required the use of broken lines in Fig. 2 .
With the fluid space thus defined, it is possible to perform the subdivision required for the numerical simulation. Images of the distribution of the resulting elements are provided in Fig. 3 . There, multiple images showing details of very small elements are displayed in the lower images. The catheter wall is shown in white and the surrounding fluid region is colored gray with black element lines. It is seen that, particularly near the catheter surface, there are very small elements that are aligned with the wall in order to compute velocity gradients at the wall–fluid interface.
Corollary images from the multi-lumen catheter are provided in Figs. 4–8 which show, respectively, the geometry of the device, an illustration of the device, the device inserted into actual arteries, and the mesh used to subdivide the fluid region. Fig. 4 is a bisected oblique view of the multi-lumen device shown so that the innards are displayed. In Fig. 4 , the therapeutic fluid flows from right to left. It is seen that the multi-lumen device includes a mixing chamber wherein the injectant is thoroughly mixed prior to exit. Downstream of the mixing chamber are multiple individual tubes, each of which carries a portion of the therapeutic fluid. The fluid exits the catheter and enters the blood stream at the injection port locations.
Fig. 5 shows an annotated computerized image of the multi-lumen catheter. In the image, flow travels from left to right until it exits from the injection ports. The diameter of the catheter is 1 mm (0.039 in.). At the injection end of the catheter, multiple 0.15-mm (0.006 in.) holes are arranged through which the injectant travels. More details are provided in Fig. 6 .
In the illustration shown in Fig. 6 , the multiple injection ports are called out and they are positioned in an arc at the end of the catheter. Also shown in the image is an off-center guidewire which is used to position the catheter in the artery. The illustration of Fig. 6 corresponds to the distal end of the catheter (right-hand side of Fig. 5 ).
To provide some perspective on the relative size of the multi-lumen device, an angiographic image is taken of it positioned within a Carotid artery ( Fig. 7 ). The image shows markers on the catheter that aid in guiding it into place. The catheter is inserted from the bottom of the image upward; the distal end of the guidewire is at the bottom.
The large multitude of elements shown in Fig. 8 was the result of an accuracy study to ensure that the number of calculation points was sufficiently dense to guarantee a highly accurate solution .
The simulations had two foci: first, to determine whether the multiple lumens would influence the dispersion of therapy agent within the artery downstream of the injection location. Second, to assess whether the surrounding inflation balloon could compress the catheter thereby reducing the diameter of the lumen(s) and potentially damaging the stem cells.
For the first part of the simulations, different flowrates, different fluid viscosity values, and the presence or absence of a balloon were investigated. For each case, the dispersion of therapeutic fluid downstream of the injection port was calculated. A listing of the cases is provided in Table 1 . The cases are labeled with “D” to signify dispersion studies.
| Case | Catheter Lumens | Balloon Inflated? | Blood Inlet Condition | Medication Viscosity (Pa-s) | Medication Flowrate (ml/min) |
|---|---|---|---|---|---|
| D1 | Single | No | Flowrate | 0.0014 | 5 |
| D2 | Single | Yes | Pressure | 0.0014 | 5 |
| D3 | Single | No | Flowrate | 0.0047 | 5 |
| D4 | Single | Yes | Pressure | 0.0047 | 5 |
| D5 | Single | No | Flowrate | 0.0014 | 10 |
| D6 | Single | Yes | Pressure | 0.0014 | 10 |
| D7 | Single | No | Flowrate | 0.0047 | 10 |
| D8 | Single | Yes | Pressure | 0.0047 | 10 |
| D9 | Multiple | No | Flowrate | 0.0014 | 5 |
| D10 | Multiple | Yes | Pressure | 0.0014 | 5 |
| D11 | Multiple | No | Flowrate | 0.0047 | 5 |
| D12 | Multiple | Yes | Pressure | 0.0047 | 5 |
| D13 | Multiple | No | Flowrate | 0.0014 | 10 |
| D14 | Multiple | Yes | Pressure | 0.0014 | 10 |
| D15 | Multiple | No | Flowrate | 0.0047 | 10 |
| D16 | Multiple | Yes | Pressure | 0.0047 | 10 |
The next part of the simulations, which deals with potential hemolysis of the cells, incorporated calculations for a candidate medication flowrate through the single-lumen catheter and another set of simulations for the multi-lumen device. For the former, the calculations listed in Table 2 were performed. All of the calculations listed in Table 2 utilized a 4 ml/min therapeutic medium flowrate. It is seen in Fig. 9 that the diameter of the single-lumen device has been sequentially reduced in size from 0.014 in. (full size) to 0.004 in. (near fully collapsed). The basis for this set of diameters will be discussed in the experimental portion of this manuscript. The cases are labeled with “SH” to reflect “Single Lumen Hemolysis” studies.
| Simulations | Dynamic Viscosity (Pa-s) | Diameter | |
|---|---|---|---|
| (in) | (mm) | ||
| SH1 | 0.0047 | 0.014 | 0.355 |
| SH2 | 0.0047 | 0.012 | 0.305 |
| SH3 | 0.0047 | 0.010 | 0.254 |
| SH4 | 0.0047 | 0.008 | 0.203 |
| SH5 | 0.0047 | 0.006 | 0.152 |
| SH6 | 0.0047 | 0.004 | 0.102 |
| SH7 | 0.0014 | 0.014 | 0.355 |
| SH8 | 0.0014 | 0.012 | 0.305 |
| SH9 | 0.0014 | 0.010 | 0.254 |
| SH10 | 0.0014 | 0.008 | 0.203 |
| SH11 | 0.0014 | 0.006 | 0.152 |
| SH12 | 0.0014 | 0.004 | 0.102 |
For the multi-lumen device, the calculations from Table 3 were performed. There, the flowrate through the device was varied from 3 ml/min to 10 ml/min and two different therapy fluid viscosities were used. Since the multi-lumen device resisted compression (confirmed by experimental measurement of the lumen diameters for various balloon pressures), all calculations were completed using a constant multi-lumen diameter. The cases in Table 3 are labeled with “MH” to denote “Multi-Lumen Hemolysis” studies.
| Simulation | Dynamic Viscosity (Pa-s) | Flowrate (ml/min) |
|---|---|---|
| MH1 | 0.0047 | 3 |
| MH2 | 0.0047 | 4 |
| MH3 | 0.0047 | 5 |
| MH4 | 0.0047 | 6 |
| MH5 | 0.0047 | 7 |
| MH6 | 0.0047 | 8 |
| MH7 | 0.0047 | 9 |
| MH8 | 0.0047 | 10 |
| MH9 | 0.0014 | 3 |
| MH10 | 0.0014 | 4 |
| MH11 | 0.0014 | 5 |
| MH12 | 0.0014 | 6 |
| MH13 | 0.0014 | 7 |
| MH14 | 0.0014 | 8 |
| MH15 | 0.0014 | 9 |
| MH16 | 0.0014 | 10 |
In summary of the simulations, a total of 16 individual cases were performed covering both the single- and multi-lumen devices to assess the therapeutic dispersion performance. Next, 12 simulations were performed on the single-lumen device with different lumen diameters to determine whether mechanical hemolysis will occur. Finally, 16 calculations were completed for the multi-lumen device with various flowrates to test whether mechanical hemolysis occurs during its use.
In the Results section of this manuscript, all outcomes of the simulations will be provided.
2.2
Experimentation
The experiments had two main phases. First, a series of benchtop tests was performed to measure the open lumen diameter with various balloon inflation pressures. The measurements were made with highly accurate pin gauges inserted into the catheter following the inflation of the balloon. It was found that the lumen diameter decreased as balloon pressure increased. Fig. 9 exemplifies the results. Shown there is the single-lumen catheter with four images corresponding to four different balloon pressures. For the lower pressures, the lumen is clearly larger; however, as the pressures increases, there is a visible contraction.
The collapse was quantified with pin-gauge measurements for pressures from 0 atm to 10 atm; the experiments are discussed in . These values of compressed single-lumen diameters were subsequently used in the numerical simulations which have already been discussed ( Table 2 ). Similar experiments were performed on the multi-lumen device; however, no measureable decrease was found in the lumen spaces. This resistance to compression is a feature of the multiple lumen design and the wall structure.
The second part of the experimental investigation was a measurement of cell viability as therapeutic fluid is passed through the two catheter designs. Solutions with 5 × 10 6 /ml Mesenchymal Stem Cells (MSCs) were employed. The cells used were human allogenic mesenchymal bone marrow derived; seven replicate experiments were performed on each device. The viscosity of the carrying fluid was measured to be 0.003 Pa-s which is bounded by the two values already discussed in the prior section. After flushing the catheters with saline, 0.35 cubic cm of solution was injected through the devices at a controlled 1 ml/min or 4 ml/min flowrate. Then, another saline flush was performed. Viability of cells before and after passing through the devices was obtained using trypan blue.
2
Materials and methods
By way of an overview, this study involved multiple stages and analysis tools. First, numerical simulations were carried out for the fluid flow in both catheters. The simulations provide detailed information on the flow characteristics for both devices, including pressure, shear stress, transition time, and velocity within the fluid. These data were used to determine the likelihood of mechanical hemolysis of the stem cells as they passed through the device.
Second, independent experiments were performed to characterize the catheter compression for various balloon inflation pressures and this information was used to evaluate the likelihood of cellular injury during injection. Comparisons were then made between the experimental and simulated results; it was found that there was excellent agreement.
2.1
Simulations
The simulations refer to an established flow analysis tool termed computational fluid dynamics. This analysis methodology refers to the solution of complex flow problems by subdividing the fluid region into a large multitude of regularly shaped elements (sometimes called cells or volumes). At each element, basic equations conserving mass, momentum, and species are solved. The outcome of these calculations is a continuous variation of flow parameters (such as pressure, velocity, density, stress, etc.). For the present study, the selected single-lumen catheter was a Trek Coronary Dilatation Catheter (Abbott Vascular, Santa Clara, CA). The alternative multi-lumen device is the FlowFusion™ ND® Infusion Catheter (Cook Regentec, Indianapolis, IN).
For both devices, the first stage of the simulation process was the creation of a digital representation of the physical device. For the single-lumen catheter, Fig. 1 provides a display of the digital rendition.
