Background
Eighty-seven percent of strokes are acute ischemic strokes (AIS) caused by the thickening of blood in the artery which blocks the blood supply to the brain [1]. The blockage causes reduced oxygen and blood to the brain leading to damage to the brain, ultimately leading to long-term disabilities [2]. The most common treatment for AIS is thrombectomy but only ten percent of patients treated make a full recovery [3].
UN&UP has proposed a new solution for treating AIS with an improved quality of life post-treatment. Under the leadership of Mike Sabo, the CPO, UN&UP will utilize a vascular phantom for nanoparticle testing to develop a novel method of thrombolysis. The goal of the vascular phantom is to create a more effective and safer way to treat AIS, compared to the more invasive thrombectomy. Therefore, there is a need to create a vascular phantom for simulating the delivery of a consistent concentration of nanoparticle infusions to an intra-arterial or intravenous line that reduces the possibility of adverse reactions for patients with an acute ischemic stroke (AIS) event.
The prototype created will provide a way to test the delivery of nanoparticles by stimulating blood flow, avoiding the need to test on humans or animals. The infusion of nanoparticles needs to be efficient in targeting the site, preventing side reactions in the body. The phantom will monitor the delivery of the nanoparticles, which will be similar to an in-vivo environment via temperature and flow rate. This will allow other clinicians or researchers when experimenting with other drug delivery through an intra-arterial or intravenous line.
The direct stakeholder is UN&UP, which of whom is also the group’s client that directed the development of the current device. Indirect stakeholders include clinicians who are involved in the process by sharing their expertise and patients who could potentially benefit from this device in the future. Other indirect stakeholders include researchers if this device were put on the market due to how this device is targeted towards simulating the delivery of drugs or nanoparticles intravascularly through an intra-arterial or intravenous line.
Description of Solution
The chosen solution is a single-pass vascular phantom that starts in the reservoir, where a glycerine-water solution (60/40 ratio by volume) will be heated with a sous vide machine to 37°C. Once heated to the correct temperature, the peristaltic pump flow rate is set to either 300 ml/min or 400 ml/min depending on if the cubital/cephalic vessel or the carotid vessel is connected, respectively. The pump is allowed to run until the velocity profiles inside the vessel have stabilized and there are no remaining air bubbles, which may take a few minutes. The glycerine solution will pass through fluid-tight ports and silicone tubes to the vessel and injection site. As the glycerin solution continues to flow constantly, the nanoparticles will be injected by a syringe pump at a constant rate between 1 to 5 ml/min into the chosen vessel. The webcam is mounted in front of the vessel where it captures the two plane view, which is achieved by a mirror mounted at a 55° angle. Finally, the nanoparticles now combined with the glycerin solution exit the vessel through another silicone tube into a waste container. Figure 1 depicts the entire single-pass flow system that has been chosen as the solution. Each vessel is 3D printed and includes an insertion site for a catheter that leads to the nanoparticle injection site seen in Figures 3 and 4 in Appendix I. The temperature and Raspberry Pi were not used since there wasn’t any significant change in temperature in the waste. The service manual, located in Appendix II, contains an overview of the intended use and an instruction manual, which also describes the setup of the device.
The peristaltic pump was commercially purchased on Amazon. The flow pump had an expected flow rate from 250 ml/min to 600 ml/min. However, it was not possible to set the precise flow rate, as it was set by an unlabeled adjustable knob. Therefore, an experiment was run to determine the specific flow rate, which also served as a verification test for the flow rate. As shown in Figure 2, the dial was labeled with colored tape, with each color representing a different flow rate. The four different flow rates were in the range of the desired 300 ml/min for the median cubital/cephalic vein and 400 ml/min for the carotid artery.
Two different sizes of the vessels were created: the median cubital/cephalic vein has an inner diameter (ID) of 2.5 mm and an outer diameter (OD) of 3 mm. The carotid artery has an ID of 6 mm and an OD of 6.5 mm. The vessels were 3D printed using clear v4 resin on a Formlabs Form 3 printer. Initially, silicon tubing were planned for the vessels; however, the addition of an injection port made the silicon not a viable option as the silicon tube was not able to consistently hold the inject port without leaking. The use of clear rigid resin seemed a more viable option as it was able to provide higher printing resolution of the vessels and an injection port could be added without leakage. Transparency was achieved by sanding the vessels and then coating them with a polycrylic protective finish. Male and female Luer locks were added on the ends of the vessels so the tubing system could easily be connected while being fluid-tight.
The vessel housing system and camera bed were also 3D printed with clear v4 resin using a Form 3 printer. A housing system to allow a white color in the backdrop of the vessels was requested to achieve a better view of the nanoparticle injection. Clear resin was also used to allow illumination onto the vessels from the LED light panel underneath. Furthermore, by the use of 3D printing, precision and constant placement of the vessels with easy viewing of the two planes through a mirror was achieved. The CAD models of the mirror holder and camera bed are depicted in Figures 13 and 15 in Appendix V, respectively.
The injection port was added directly to each vessel system. Two different types of catheters were used for the injection of the nanoparticles: BD Insyte Autoguard Catheter and BD Nexiva Diffusics IV Catheter. The CAD models in Figures 9 and 11 of Appendix V represent the BD Insyte Autoguard catheter for both the cephalic vein and carotid artery. These two differ in design, subsequently varying the design of the vessel systems. Therefore, Figures 10 and 12 in Appendix V show the different CAD models for the cephalic vein and carotid artery with the BD Nexia Diffusics catheter injection site. The injection site is angled at 30° degrees to simulate an actual catheter when injected into a patient. Each vessel and injection site is attached to a slider seen in Figure 14 of Appendix V for easy insertion into the mirror holder.
Verification
The completed verification plan is detailed in Table 1 in Appendix I, which is slightly modified from the plan presented in the V&V Paper. Several specifications were removed due to redundancies as the microprocessor was removed. There is no longer any firmware or software being utilized (other than the webcam software, which was determined to not need verification), so the firmware and software specifications were removed. The specification for surge protection was also removed since there is also no longer any circuitry involved in the prototype. The first verification test done was to verify several specifications at once (SDS01, CDS02, PDS05, and PDS04; see Table 1). Images were captured by the webcam software during nanoparticle injection. The images represented in Figures 3 through 8 in Appendix III showed clear visibility of the nanoparticle injection; therefore, the specifications were verified.
The second verification test, the temperature experiment, entailed heating up the reservoir fluid to human body temperature. Every five minutes, the temperature was checked on an analog thermometer to verify that the temperature sensor in the heating system was accurate. The test was successful, as the heating system did display accurate temperatures.
The next verification test was the flow rate experiment which determined the flow rate of several locations on the pump knob. First, the pump was run for several minutes to stabilize the velocity profile. Once the flow stabilized, water was pumped into a beaker for five minutes. The volume in mL was recorded and divided by the time to calculate the flow rate in mL per minute as shown by the following equations:
where the four flow rates were labeled as red, white, green, and yellow in increasing order. Each color is marked on its prospective location on the pump flow rate knob seen in Figure 2. This process was repeated four times, gradually increasing the flow rate dial on the pump each time. This experiment was repeated on a different tubing size, and the difference in flow rates was negligible; therefore, the flow rate marks on the pump dial are applicable to any tubing size selected.
The waterproofing plan was verified during the validation test run (see Validation Section). Since the validation plan entailed an extended runtime, the waterproofing specification was verified during this runtime. All tubings and ports remained fluid-tight during the duration of the test run as expected, so the waterproof specification was verified.
The budget was verified after the completed parts and buy list were completed. After calculating the final budget in Appendix IV, it was determined that the project was completed under budget. Likewise, the timeline specification was verified through the deliverables being supplied on time.
Validation
Validation of the product was achieved through a one-hour test run, as specified in the V&V report. The validation test run is required to make sure all the components work together to satisfy the client’s needs for the product. The client has determined that there would be no need to run the device for over an hour at a time, so a test run of one hour will be sufficient to test the durability of the device components. All systems were being utilized in the way they would be during a real test run—that is, the glycerine solution was utilized instead of testing with water. This made sure that the thicker glycerine solution interacted properly with the heating and vessel systems. During the test run, all components were checked periodically to make sure they were continuously functioning and interacting with each other properly. The validation test run was successful, as all systems and components functioned as required by the customer’s needs. The client also verbalized to the team after a demonstration of the device that it meets all requirements, which further showed proof of validation.
FDA Requirements
This product is intended for use in gathering data simultaneously with other vascular phantoms made by the client that are aimed to support a future device produced by UN&UP during the FDA approval process. The goal for the creation of the phantom is to be economical and produce consistent and clinically representative results [4]. Nonetheless, UN&UP should address the technical considerations as part of fulfilling Quality System (QS) requirements since part of the device was made by additive manufacturing. It is likely the vascular phantom is a class I device exempt from the requirement to submit a premarket notification 510(k); however, select class I devices need to maintain procedures to control the devices’ design as per 21 CFR 820.30 to ensure the specified design requirements are met [5]. This is to make certain that 3D printed devices can perform as intended. Whether the device is 510(k) exempt or not, it is important to note the device may not also be exempt from compliance with QS requirements [6].
All in all, it is probable the vascular phantom is a class I device and exempt from a 510 (k) because it will not be used in animal or human clinical trials, endanger the safety or health of any one person, nor contaminate any device that will be used in clinical trials. Due to the aim of the device residing in testing rather than commercial distribution, it is highly possible the device will be 510(k) exempt. Secondly, the lab station and device need to fall under the regulation of the Occupational Safety and Health Administration (OSHA). UN&UP follows all the criteria under OHSA and the device is also following the OSHA regulation. The device is a non-invasive device that uses non-harmful devices. All the chemicals used, glycerin, PBS, and iron nanoparticles, can be poured down the drain since the chemicals are not harmful to the pipe system.
Therefore, UN&UP is not currently in an FDA approval process for the specific product made for testing the nanoparticle infusion in a cephalic vein and carotid artery because it is not being marketed to the public. Furthermore, since it is not FDA approved, the product will not need a MAUDE search. Regardless, proper documentation of the inspection, measuring, test equipment, and calibration standards should be upheld to maintain the accuracy and fitness of the device as per 21 CFR 820.72 [7].
Design Safe
When conducting a DesignSafe analysis [8], the biggest risks stem from the likelihood that fluid will leak either from the ports of the tubes, disconnected tubes, or the injection sites into the electrical component outlets. The electrical components that could put the user at risk of electrical shock from water damage include the webcam, LED light board, and both the peristaltic and syringe pump. Active monitoring of the device and proper handling of care largely eliminate these risks, but understanding that human error cannot be eliminated, it is imperative to reiterate the importance of proper handling and setup. Otherwise, there does not appear to be anything else about the device that could encompass a major risk to any potential future user.
Proper handling of the device will also reduce the threats of hazards with a risk level of both low and medium. Similarly, with conscious monitoring of the device and preparedness, it is likely to pose a low threat to the user. To remind the user of the potential issues that could occur from negligence, guidelines were recapitulated in the full DesignSafe Output that can be found in Appendix VI. The guidelines aim to advise the user on how to safely use the device during normal operation, when loading and unloading, transporting materials, and during clean up. They also aim to advise the user on how to better reduce the risk for non-users that are passing by. With the device requiring multiple outlets and taking up a large amount of space, there is a low risk that a person passing by could trip on a cord or bump into a reservoir by accident.
Conclusions
Our needs statement called for a vascular phantom to simulate a consistent concentration of nanoparticle infusions intravascularly, and our group was able to deliver a device to meet such a need. The syringe pump was correctly configured to deliver a consistent amount of nanoparticles over a specified time. The printed phantom vessels allowed for visualization of the infusion while maintaining the accurate sizes of the median cubital/cephalic vein and carotid artery. Therefore, all current design specifications were met. The proper implementation of the device components was confirmed after successful verification and validation of the device, and positive feedback from our client.
If this project were to continue to progress in the future, it would be our job to further develop software to aid in analyzing the characteristics of the nanoparticle injection. To start, it was suggested that we use video processing software to enhance the view of the nanoparticles as they are injected into the vessel and flushed out by the peristaltic pump. There are multiple ways to conduct video processing, but considering our skills and intent, we would likely use Matlab. Typically, video applications require flexible analysis and processing functionality, but by using Matlab we would have the ability to develop solutions to video stabilization, target detection, and object tracking. By downloading an Image Processing Toolbox, we could begin with image segmentation, image enhancement, and image registration. From there we could learn the best way to visualize the flow of nanoparticles and apply it directly to the video taken from the webcam. Furthermore, with video viewer apps included in Matlab, the video of the nanoparticle injection could be viewed as an image sequence which would allow the frames to be viewed in multiple different ways. Namely, it could be largely beneficial to specify a colormap to apply various intensity values. A stark contrast between the nanoparticles and the backdrop of the vessel would aid largely in calculating the velocity profile.
Were this project to be repeated, we would want to focus on the precision of all catheter injection sites, enhancing the transparency of the vessels, and increasing the tolerance on the vessel sliders for stability. By increasing the precision of the catheter injection site, we could hope to better mimic the way a catheter rests in a human vessel. Currently, it seems to have a decent amount of movement when the flow rate is increased. Similar to the catheters, the sliders that hold the vessels move quite freely. If they were more secured in the mirror holder, that increases the chance that the focus remains on the vessels and decreases the risk of the tubes causing it to wobble. Lastly, it would be beneficial to slightly better the angle of the mirror to allow for a closer two plane view of the nanoparticle injection.
Over the course of the prototype and design process, all group members had the opportunity to learn what it feels like to work at a startup funded by NIH grants. Each member conducted research to understand the problem, gained knowledge about the novel nanoparticles to be used, and determined what the best possible solution would be. All students involved worked together as if we were a team employed by UN&UP to create a design to further add to the research already done by the company and propel them forward. It was vital to understand the design process as many iterations and client meetings were done to finally reach the end goal. Overall, our knowledge is increased in the areas of fluid flow, rapid prototyping, and nanoparticle movement throughout the body’s vessels.
There are several components that contain IP in our design. For example, the webcam used for infusion monitoring is trademarked by Depstech. Another example of IP in the design is the sous vide which are used as the heating system. This is a patented product (international patent # WO2015154886A3). The Luer locks used to connect the tubing system were patented in Europe (an example Luer lock patent number is EP0869826B1). Most other tubing and catheters were also protected either by patent or trademark. Since the majority of this device is a combination of commercially available products and the outcome is simply visualization, it would not be worth pursuing any sort of IP at the current time. If in the foreseeable future the device were to be connected to multiple software to aid in configuring the velocity profile of the nanoparticles or document instantaneous flow rate and temperature output, it might be worth it but still would not be necessary. Ultimately, it would be best to pursue a patent when this device is used in conjunction with other devices that come together to make a full product and aid the goal of lysing occlusive clots faster and more reliably. Moreover, since this device is currently designed for testing to obtain data to be used as supporting material for another product, there are no direct human or animal trials. Additionally, the usage of this device does not affect the user in any negative sense that can be determined from our testing. Therefore, there is no evidence to believe there are any unethical considerations within our device.
Works Cited
[1] J. L. Hinkle and M. M. Guanci, “Acute ischemic stroke review,” J. Neurosci. Nurs., vol. 39, no. 5, pp. 285–93, 310, 2007.
[2] E. Hersh, “Ischemic stroke: Symptoms, treatment, recovery, and more,” Healthline.com, 22-Sep-2017. [Online]. Available: https://www.healthline.com/health/stroke/cerebral-ischemia. [Accessed: 29-Sep-2021].
[3] “Treatments,” Org.uk, 04-Dec-2017. [Online]. Available: https://www.stroke.org.uk/what-is-stroke/diagnosis-to-discharge/treatment. [Accessed: 29-Sep-2021].
[4] Center for Devices and Radiological Health, “Phantoms,” U.S. Food and Drug Administration, Feb. 8, 2019. [Online]. Available: https://www.fda.gov/radiation-emitting-products/nationwide-evaluation-x-ray-trendsnext/phantoms. [Accessed: Mar. 2, 2022].
[5] 21CFR820.3 “CFR – Code of Federal Regulations Title 21.” U.S. Food and Drug Administration, Jan. 6, 2022. [Online]. Available: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=820.3 [Accessed: Mar. 2, 2022].
[6] A. Hampshire, “Technical considerations for additive manufactured medical devices guidance for industry and food and drug administration staff,” Fda.gov, 2017. [Online]. Available: https://www.fda.gov/media/97633/download. [Accessed: Mar. 2, 2022].
[7] 21CFR820.71 “CFR – Code of Federal Regulations Title 21.” U.S. Food and Drug Administration, Jan. 6, 2022. [Online]. Available: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=820.72 [Accessed: Mar. 2, 2022].
[8] Rathje, E., Dawson, C. Padgett, J.E., Pinelli, J.-P., Stanzione, D., Adair, A., Arduino, P., Brandenberg, S.J., Cockerill, T., Dey, C., Esteva, M., Haan, Jr., F.L., Hanlon, M., Kareem, A., Lowes, L., Mock, S., and Mosqueda, G. 2017. “DesignSafe: A New Cyberinfrastructure for Natural Hazards Engineering,” ASCE Natural Hazards Review, doi:10.1061/(ASCE)NH.1527-6996.0000246.
Appendix
I: Design Specifications
Table 1: Verification Results.
| Verification Test | Specification Verified | Verification Results |
| Capture images of nanoparticle visibility through observation window | SDS01: Infusion Delivery Monitoring CDS02: Observation Window PDS05: Catheter PDS04: Vessel System | Infusion properly visualized |
| Temperature Verification Experiment | SDS02: Temperature Sensors PDS02: Heating System | Heat system temperature sensor verified with analog thermometer |
| Flow Rate Experiment | PDS03: Pumping System | 4 different flow rates determined |
| Waterproof Experiment | CDS01: Waterproofing | Verified during validation |
| Budget | GDS03: Budget | Budget compilation reported under budget |
| Timeline | GDS04: Timeline | Prototype delivered on time |
| Removed Specifications | SFDS01: Firmware SFDS02: Software GDS02: Surge Protection | N/A |
II: User Manual
1.0 Intended Use
1.1 This device is intended for engineers and researchers testing nanoparticle infusion using an intravenous or an intra-arterial line. This product is not intended for patient use and is not to be used in clinical settings. It is for gathering supporting data and testing purposes only.
2.0 Set-Up
2.1 Mix the 64-ounce bottle of 99.7 glycerin with 96 ounces of water in a large container, insert the heating apparatus, and set the temperature to 37°C.
2.2 Connect the LED light panel, webcam, peristaltic pump, and syringe pump to appropriate power sources. Place the webcam in the camera bed holder on the LED light panel.
2.3 Select either the carotid or cephalic sized vessel and connect the silicone tube to the peristaltic pump. Slide the vessel into the mirror holder making sure the tubes are not twisted. Make sure the flow from the peristaltic pump will be in the same direction as the flow of the nanoparticle injection. Insert the mirror holder with the vessel in the camera bed holder.
2.4 Put the remaining tube from the other side of the vessel into a waste reservoir and cover gently with a lid.
2.5 Fill a disposable syringe with 5 ml of nanoparticles and 30 ml of PBS solution. Set the syringe pump to account for the diameter of the syringe and select a flow rate in the range of 1 to 5 ml/min for a 30 ml infusion. Attach the syringe to the syringe pump.
2.6 Connect one side of the IV catheter line to the catheter in the vessel’s nanoparticle injection site and the other side to the disposable syringe.
2.7 Turn on the peristaltic pump to ~300 ml/min or ~400 ml/min for either the cephalic or the carotid artery, respectively. Let run for up to 5 minutes to rid the vessel of bubbles; increase or decrease the speed accordingly if needed.
2.8 Turn on the syringe pump and start recording as necessary from the webcam. Once the syringe pump is turned on, it is important to rock the syringe pump from side to side. Doing so will mix the nanoparticles in the solution, prevent clumping, and ensure a steady injection through the flow of the vessel.
2.9 Turn off both pumps once the injection from the syringe pump is complete.
3.0 Safely discard the iron oxide nanoparticles down the drain. Do not reuse.
3.0 Care Instructions
3.1 Before each use, the silicone tubes, connecting ports, resin vessels, and reservoirs should be examined for any damages or breakage. This will prevent excessive or uncontrollable leakage when initially starting the device.
3.2 Vessels should be handled with caution. Due to the thin wall thickness and rigidity when connecting to and disconnecting from the peristaltic pump, they are easily susceptible to fracture. Similar applies to the injection site when connecting the IV line to the syringe pump from the respective catheters.
3.3 The tubes and vessels should be flushed with water or glycerin solution to prevent the build-up of nanoparticles ultimately preventing any blockage from occurring.
4.0 Safety Hazards
4.1 Monitor the device at all times while it is operating. Any leakages create a high risk of electrical shock and damage to electrical components. Minor leakage is normal when changing the vessels, be mindful of the glycerin solution exiting the tubes.
4.2 Multiple components require power from a wall outlet; do not overload the circuit and only use outlets designed to handle multiple plugs. Secondly, do not leave cords unmarked or uncovered in a walkway to prevent falls from those passing by.
4.3 Always keep a lid on both reservoirs to prevent excess spillage of liquid and waste. This also prevents components from falling into the reservoir and contaminating it.
III: Nanoparticle Infusion Captures
Figure 6: Nanoparticle Injection through BD Insyte Autoguard Catheter, Carotid Vessel.
IV: Budget
Table 2: Bill of Materials Used
| Designator | Component | Number | Cost per unit | Total Cost | Source of Materials |
| Webcam | DEPSTECH DW49 HD 8MP | 1 | 69.99 | 69.99 | Amazon |
| Glycerin | SMPLY 99.7% Pure USP | 1 | 24.99 | 24.99 | Amazon |
| Peristaltic Pump | Kamoer KCP600 24V | 1 | 99.54 | 99.54 | Amazon |
| Heat Source | Sous Vide 1200W IPX7 | 1 | 49.99 | 49.99 | Amazon |
| Silicone Tubes | High-Temp Soft Rubber Tubing | 10 ft | 17.10 | 17.10 | McMaster-Carr |
| QOSINA Connectors | Male Luer Lock | 25 pack | 13.30 | 13.30 | QOSINA |
| QOSINA Connectors | Female Luer Lock | 25 pack | 12.40 | 12.40 | QOSINA |
| LED Light Panel | A4 Light Box tiktecklab | 1 | 19.78 | 19.78 | Amazon |
| Vessels, Mirror Holder Camera Bed | Custom Components | 3 | – | – | Printed on a Form 3 |
| Closed IV Catheters | BD 24 GA 0.75 IN (0.7x19mm) | 25 pack | 87.00 | 87.00 | eSutures |
| Shielded IV Catheter | BD 20 GA 1.16 IN (1.1x30mm) | 50 pack | 109.00 | 109.00 | eSutures |
| Temperature Sensor | Zacro LCD Digital | 1 | 7.99 | 7.99 | Amazon |
| Polycrylic | Clear Satin Polyurethane | 1 | 11.98 | 11.98 | Lowes |
Table 3: Bill of Materials Purchased
| Designator | Component | Number | Cost per unit | Total Cost | Source of Materials |
| Webcam | DEPSTECH DW49 HD 8MP | 1 | 69.99 | 69.99 | Amazon |
| Glycerin | SMPLY 99.7% Pure USP | 1 | 24.99 | 24.99 | Amazon |
| Peristaltic Pump | Kamoer KCP600 24V | 1 | 99.54 | 99.54 | Amazon |
| Heat Source | Sous Vide 1200W IPX7 | 1 | 49.99 | 49.99 | Amazon |
| Temperature Sensor | Zacro LCD Digital | 1 | 7.99 | 7.99 | Amazon |
| Housing Materials | Langaelex Acrylic Sheets | 1 | 9.99 | 9.99 | Amazon |
| Peristaltic Pump | 12V High Flow TOPINCN | 1 | 45.18 | 45.18 | Amazon |
| Raspberry Pi | Raspberry Pi 4 Model B 2GB | 1 | 99.99 | 99.99 | MicroCenter |
| Motor Drivers | Bojack L293D 16-Pin | 10 pack | 8.99 | 8.99 | Amazon |
| Temperature Sensor | DS18B20 Module Kit | 3 | 8.99 | 26.97 | Amazon |
| Total: | $443.62 |
V: Mechanical Drawings
Figure 15: Holder to keep the camera and mirror holder in place for a consistent focus on the vessels during nanoparticle injection.
VI: Design Safe
See the full Design Safe Analysis underneath the Final Solution section.