In Vitro models for thrombogenicity testing of blood-recirculating medical devices

ABSTRACT

Introduction: Blood-recirculating medical devices, such as mechanical circulatory support (MCS), extracorporeal membrane oxygenators (ECMO), and hemodialyzers, are commonly used to treat or improve quality of life in patients with cardiac, pulmonary, and renal failure, respectively. As part of their regulatory approval, guidelines for thrombosis evaluation in pre-clinical development have been established. In vitro testing evaluates a device’s potential to produce thrombosis markers in static and dynamic flow loops.

Areas covered: This review focuses on in vitro static and dynamic models to assess thrombosis in blood-recirculating medical devices. A summary of key devices is followed by a review of molecular markers of contact activation. Current thrombosis testing guidance documents, ISO 10993–4, ASTM F-2888, and F-2382 will be discussed, followed by analysis of their application to in vitro testing models.

Expert opinion: In general, researchers have favored in vivo models to thoroughly evaluate thrombosis, limiting in vitro evaluation to hemolysis. In vitro studies are not standardized and it is often difficult to compare studies on similar devices. As blood-recirculating devices have advanced to include wearable and implantable artificial organs, expanded guidelines standardizing in vitro testing are needed to identify the thrombotic potential without excessive use of in vivo resources during pre-clinical development.

KEYWORDS:

• Blood compatibility
• blood-recirculating medical devices
• dynamic thrombosis models
• hemocompatibility models
• static thrombosis models
• thrombogenicity
• thrombosis

Article Highlights

• Thrombosis testing markers vary across studies and no one testing marker can provide a complete picture of the level of thrombosis due to blood contact with a device.

• Static models can provide a method to study thrombosis due to blood-material interaction but are limited in use for evaluation of whole devices due to the lack of flow.

• Dynamic models, while allowing for an overall evaluation of thrombosis due to blood contact with the device material and flow path, are highly unstandardized.

• In 2019, nearly 60 years after the first significant dynamic flow loop, the Chandler loop, was developed, medical device thrombosis testing is still burdened by the lack of a standardized set of in vitro static and dynamic tests that allow for the thorough evaluation of thrombosis in vitro.

• As blood-recirculating medical devices become more advanced and require longer blood exposure, better and more consistent thrombosis testing models are required. These studies will be able to compare and evaluate new devices while minimizing the use of animal studies.

Acknowledgments

The authors gratefully acknowledge the advice and contributions of Zohora Iqbal of UCSF. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the HHS or FDA.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by FDA grants U01FD004979 and U01FD005978, which supports the UCSF-Stanford Center of Excellence in Regulatory Sciences and Innovation. Additional support from NIH/NIBIB grants U01EB021214 and U01EB025136 is also acknowledged.