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Large Diameter Flow Loop for In Vitro Dynamic Thrombogenicity Testing

Catalog of Regulatory Science Tools to Help Assess New Medical Devices 

This regulatory science tool (RST) provides a step-by-step protocol to design a 9.5 mm inner diameter recirculating flow loop test system and perform bench-top thrombogenicity testing of catheter-like blood-contacting medical devices and materials. Additionally, this tool describes a dynamic pump occlusion setting method to improve blood flow rate consistency between different roller pumps.

Technical Description

This RST provides a step-by-step protocol to build a 9.5 mm inner diameter (ID) recirculating flow loop test system and perform bench-top thrombogenicity assessments of catheter-like blood-contacting medical devices and materials. This methodology also includes a dynamic pump occlusion setting method to improve blood flow rate consistency between different roller pumps. This 9.5 mm flow loop system was developed and evaluated based on our previously established 6.4 mm ID tubing system detailed in an RST (RST24CV10.01) titled “An In Vitro Blood Flow Loop System for Thrombogenicity Evaluation of Medical Devices and Biomaterials.” An in vitro dynamic thrombogenicity test system with larger ID flow loop allows for medical devices with larger diameters to be tested. This tool may assist users in comparing the thrombogenic potential of different device materials against appropriate control materials and comparator devices. 

Intended Purpose 

The purpose of this tool is to provide a test method to evaluate acute thrombogenicity of biomaterials and blood-contacting medical devices in a dynamic test setting. In vitro thrombogenicity test system using a larger 9.5 mm inner diameter (ID) flow loop allows for a wider range of medical device sizes to be tested. This tool can be used  to support the design, development, and safety evaluation of blood-contacting medical devices and may contribute to efforts to reduce reliance on animal studies.1

Compared with a conventional in vivo non-anticoagulated venous implant (NAVI) assay that is commonly used to evaluate acute thrombogenicity of biomaterials or devices with short-term blood contact, this in vitro flow loop test may offer several advantages: (1) utilizes donor specific heparin concentrations to account for blood reactivity variability among individual blood  donors; (2)  reduces implantation procedure related confounding factors; (3) allows for a direct comparison by using the same blood pool to evaluate different materials/devices in a paired test fashion; and (4) does not require animals to be sacrificed.

This RST is part of a family of invitro thrombogenicity testing tools Please refer to existing RST (RST24CV10.01) for the 6.4 mm ID flow loop test system.  This 9.5 mm ID flow loop test system is an addition to RST24CV10.01, designed for testing devices that are too large for the 6.4 mm ID flow loop test system,  as studies have shown that the ratio of device to vessel diameter can significantly affect thrombus formation.2-4.  Evaluating a device with a too large or to small diameter for the flow loop may increase the risk of false positive or false negative results, respectively.

Testing

The usage of this tool has been verified in a study published in the article “Development of a large diameter in vitro flow loop thrombogenicity test system” by Serna et.al.3  Using a dynamic roller pump occlusion setting method, a 9.5 mm ID flow loop test system was developed for thrombogenicity evaluation of medical device materials.  In the verification study, the large diameter flow loop test system distinguished thrombogenic materials (latex and BUNA) from those with low (PTFE) and intermediate (3D-printed nylon and silicone) thrombogenic potentials.

Limitations

The technical limitations of the RST are described in the peer-reviewed publication “Development of a large diameter in vitro flow loop thrombogenicity test system” by Serna et.al.5 Briefly, this test is an assessment of acute thrombogenicity and thus it is primarily intended for evaluating thrombogenicity of devices with a blood contact duration less than 24 hours. While the test is capable of differentiating thrombogenic materials and thromboresistant ones, it may not be sensitive enough to distinguish among commonly used biomaterials with subtle differences in thrombogenicity. Only smooth catheter-like materials with a diameter of 3.2 mm were evaluated in this flow loop test system. 

Supporting Documentation

A detailed description of this tool is provided in the User Manual.

Relevant standards and publications include:

  1. Guidance for Industry and Food and Drug Administration Staff. Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process": US Food and Drug Administration, Silver Spring, MD 2023. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/use-international-standard-iso-10993-1-biological-evaluation-medical-devices-part-1-evaluation-and
  2. ISO 10993-4: biological evaluation of medical devices part 4—selection of tests for interactions with blood. 2017.
  3. Serna et al. Development of a large diameter in vitro flow loop thrombogenicity test system. Artif Organs. 2024. doi: 10.1111/aor.14852.

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