Blood-recirculating medical devices like Extracorporeal Membrane Oxygenation (ECMO), also called extracorporeal life support (ECLS), play a vital role in modern healthcare, offering life-saving support to patients facing severe cardiac and/or respiratory failure. Once considered a last-resort therapy, ECMO has evolved into a cornerstone of advanced critical care, providing not only survival but also better quality of life for patients with complex conditions.
ECMO represents a beacon of hope for those in critical need, and recent innovations are propelling this technology into a new era–one defined by greater safety, efficiency, and adaptability. Breakthroughs in oxygenator design, pump technology, system miniaturization, and real-time monitoring are significantly enhancing ECMO’s clinical performance. These advances are essential to meet the growing demand for life-saving interventions and to adapt to the ever-changing landscape of intensive care medicine.
A standard ECMO system comprises several key components, including a system unit, blood drive pump, disposable consumables (membrane oxygenator, pump head, cannulas, blood circuits, and various connectors), temperature control system, air-oxygen blender, and monitoring equipment (pressure, temperature, and blood oxygen saturation sensors). Together, these components form the foundation of a sophisticated support system capable of sustaining life during critical illness. As technology continues to evolve, Extracorporeal Membrane Oxygenation systems are becoming more compact, user-friendly, and efficient, bringing new possibilities for patient care and outcomes.
Navigating Regulatory Requirements: Thrombogenicity and Hemocompatibility Testing for Extracorporeal Membrane Oxygenation (ECMO) Devices
Thromboembolism remains a serious complication associated with the use of Extracorporeal Membrane Oxygenation devices, underscoring the critical importance of comprehensive preclinical thrombogenicity testing during both in vitro and in vivo evaluations. In addition, assessing mechanical hemolysis is a key element of hemocompatibility testing, helping to ensure that ECMO systems are safe and compatible with blood-contacting environments. To support regulatory approval, well-established guidelines developed by the International Organization for Standardization (ISO), outline the necessary preclinical evaluations for thrombogenicity and hemolysis. All such testing must adhere to Good Laboratory Practice (GLP) standards to ensure scientific integrity and regulatory compliance.
While in vitro tests are valuable for early-stage screening of blood-material interactions (i.e., potential risks related to thrombosis or red blood cell damage), they may not fully predict the consequences of prolonged, repeated, or permanent exposure to blood contact. Therefore, preclinical in vivo studies, utilizing appropriate animal models, are essential. These studies are pivotal not only for assessing the safety and biological compatibility of emerging ECMO technologies, but also for evaluating their efficacy and hemodynamic effects, which are critical for ensuring patient safety in clinical settings.
These comprehensive evaluations form the foundation for regulatory submissions and are indispensable for advancing next-generation ECMO technologies from concept to clinical use.
In Vivo Model Selection for Extracorporeal Membrane Oxygenation (ECMO) Devices
Selecting an appropriate in vivo model is a critical step in the successful evaluation of Extracorporeal Membrane Oxygenation systems. Several key factors should guide the choice of model, including anatomical and physiological relevance to humans, as well as ease of use in a preclinical setting. The model must have vessel sizes compatible with the clinically intended catheters, and its blood flow rates should align with those expected in clinical ECMO use. Additionally, the downstream anatomy and vessel structure should closely resemble human anatomy to ensure accurate simulation of real-world conditions. Since thrombogenicity and hemolysis are key endpoints in these evaluations, it is essential that the model exhibits human-like hematology, biochemistry, and coagulation pathways. Another important consideration is the need for appropriate veterinary care. Furthermore, the model should be capable of adapting to the necessary restricted movements required during evaluations, ensuring that the simulated conditions closely mirror the functional limitations seen in clinical ECMO applications.
Study Design for Extracorporeal Membrane Oxygenation (ECMO) Devices
Given the complexity of Extracorporeal Membrane Oxygenation devices and their direct or indirect contact with the bloodstream and internal organs, biocompatibility testing is essential. Therefore, preclinical study designs for ECMO devices must follow a comprehensive set of guidelines, including the ISO 10993 Series (Biological Evaluation of Medical Devices) and the U.S. Food and Drug Administration (FDA) Premarket Notification 510(k) process, to ensure the study closely replicates the device’s intended clinical use. Key aspects include bracketing flow rates (both low and high) and selecting appropriate cannulation sites to accurately mimic clinical scenarios. It is also common to include comparisons with existing predicate devices, which allows for benchmarking against previously approved products. The study should focus on several critical endpoints, including device performance metrics such as flow rates, oxygenation, temperature regulation, and other operational parameters. Additionally, thrombogenic potential and hemolysis are essential aspects to evaluate. Upon completion of the study, endpoints typically include scoring thrombus formation within the device, conducting a gross inspection of device components, and performing clinical pathology and histopathological examinations. Special attention should be given to the implant site and downstream organs, with particular focus on identifying thromboembolic events. Key endpoints are summarized in the table below.
| Endpoint | Assessment |
| Thrombogenicity/ Safety | In life blood analyses of hematocrit, red blood cell count and platelets |
| Macroscopic gross examination of the device for thrombi using the thrombus formation score according to the anticoagulated venous implant (AVI) model scoring system | |
| Macroscopic (necropsy) and microscopic (histopathology) examination of downstream organs (lungs, heart, bronchial lymph nodes, liver, spleen, adrenal glands, kidneys, and brain) for the presence of thrombi or thromboembolism | |
| Hemolysis | Free plasma Hemoglobin concentration measurements |
| Functional (device) wear/ Performance | Blood flow is sufficient to obtain a target blood flow: both low (e.g., 0.5-2L/min) and high flow (e.g. 4-7L/min) rates can be tested Oxygenator blood inlet and outlet oxygen saturation (sO2) and partial pressure of carbon dioxide (pCO2) |
| Mechanical (device) failure | In life observations of oxygenator, pump head system, and console |
Selecting the right preclinical laboratory for the evaluation of novel ECMO systems is critical and requires careful consideration of the lab’s capabilities and experience. The laboratory should have a robust infrastructure in place, including an established model system, skilled perfusionists, experienced surgeons, and a dedicated research and animal care team. Additionally, it must maintain a rigorous Quality Assurance (QA) program to ensure GLP compliance, which is essential for regulatory acceptance. The presence of in-house clinical and anatomic pathology services is also important for comprehensive study support. The laboratory should have a proven track record in conducting successful Extracorporeal Membrane Oxygenation studies, with experience in evaluating both individual ECMO system components and full ECMO systems. This includes expertise in early feasibility testing as well as GLP-compliant chronic safety studies. Given the complexity of ECMO studies, perioperative and postoperative care is crucial. Staff should be highly trained and experienced in managing these intensive care studies to ensure optimal care and accurate study results.
Frequently Asked Questions (FAQ)
What is the importance of preclinical ECMO studies in the development of ECMO devices?
Simulating clinical conditions in preclinical ECMO studies is essential to ensure that the ECMO system performs as expected under realistic, patient-like circumstances. By replicating human-like blood flow rates, vessel sizes, and cannulation sites, we can better predict the system’s behavior in a clinical setting. This simulation helps to identify potential complications, such as thrombosis, hemolysis, or device malfunction, before human trials begin. It ensures that all possible risks are assessed, providing valuable data for both device improvement and regulatory approval.
What are the challenges in selecting the right animal model for preclinical ECMO studies?
Selecting the right animal model for preclinical ECMO studies presents several challenges. The model must closely mimic human anatomy and physiology, including blood flow rates, vessel sizes, and coagulation pathways. Porcine and ovine models are commonly used due to their cardiovascular similarity to humans, but even within these species, variations in size, health, and genetics can affect study outcomes. Additionally, the model must be able to tolerate the prolonged nature of ECMO support and provide accurate data on both short-term and long-term device performance. Balancing these factors is critical to ensuring that the study results are both reliable and translatable to human clinical use.
What role does thrombogenicity play in preclinical ECMO studies, and how is it evaluated?
Thrombogenicity is a key endpoint in preclinical Extracorporeal Membrane Oxygenation studies, as it evaluates the device’s potential to induce clot formation, which can lead to serious complications such as embolism or device failure. It is assessed through both in vivo and in vitro methods, focusing on thrombus formation within the ECMO circuit. Researchers monitor the device for the presence of blood clots, typically through direct visualization, and measure blood coagulation markers. Histopathological examinations of the ECMO circuit and downstream organs are performed to confirm whether thromboembolic events have occurred. Evaluating thrombogenicity ensures that the ECMO system is safe for long-term use and does not pose undue risk to patients.
How do preclinical ECMO studies ensure the safety of long-duration device use?
To ensure the safety of ECMO devices for long-duration use, preclinical studies include chronic safety assessments that simulate extended periods of ECMO support. These studies test how the device performs over days, weeks, or even months, under conditions that mirror clinical scenarios. Critical aspects like anticoagulation, hemodynamics, and organ function are continuously monitored. Animals undergo intensive perioperative care, with 24/7 monitoring of key parameters such as system pressures, oxygenation levels, and device functionality. This comprehensive monitoring allows researchers to identify early signs of complications such as blood clotting or device malfunctions, ensuring that the ECMO system remains safe for prolonged use in humans.
How do preclinical ECMO studies contribute to regulatory approval processes?
Preclinical ECMO studies are foundational to the regulatory approval process, as they provide the data necessary to demonstrate the safety, performance, and biocompatibility of ECMO devices. Regulatory agencies, such as the U.S. FDA and European Medicines Agency (EMA), require robust data from these studies to assess the device’s risk profile and effectiveness. By adhering to international standards such as ISO 10993-4:2017, preclinical studies evaluate key factors like thrombogenicity, hemolysis, and hemodynamic stability. This data, along with detailed reports on the device’s design and testing procedures, is critical for submitting a successful regulatory dossier. Ultimately, these studies help ensure that ECMO devices meet the required safety standards before advancing to human clinical trials.
Why Choose NAMSA?
At NAMSA Diest, we have conducted in vivo preclinical ECMO studies in compliance with ISO 10993-4:2017 and FDA guidelines, utilizing both veno-arterial (V-A) and veno-venous (V-V) methods. In collaboration with Dr. Patrick Weerwind, an experienced scientist/perfusionist, we have developed and optimized a chronic ECMO model that allows for efficient handling, easy sampling, and secure fixation in awake animals. This model also enables the animals to move freely and interact with conspecifics, ensuring a more natural environment.
Over the years, we have implemented numerous improvements not only to optimize study design and outcomes, but also to enhance animal welfare. A key aspect of our work is the establishment of a comprehensive perioperative treatment and care system, which is critical for the success of long-term duration studies. This includes a dedicated intensive care unit with 24/7 anticoagulation and hemodynamic monitoring.
Since 2016, we have successfully completed 26 preclinical ECMO studies, ranging from feasibility assessments to chronic safety and thrombogenicity studies required for regulatory approval. These studies have involved testing cannulas, oxygenators, sensors, and complete ECMO systems for MedTech companies across Asia, Europe, and the U.S. We take great pride in our expertise and our contributions to the ongoing innovations and technological advancements in the ECMO field.
