Thrombogenicity-Reducing Coatings - An Overview

Introduction

Thrombogenicity, the tendency of materials to promote blood clot formation, is a critical concern in the field of medical devices. The development of thrombogenicity-reducing coatings has emerged as a pivotal solution to enhance the safety and efficacy of various medical implants and devices. These coatings are crucial in reducing the risk of thrombosis (formation of a blood clot inside a blood vessel or heart), improving patient outcomes, and extending the lifespan of implanted devices. This article briefly explains thrombogenicity, how medical devices initiate it, the coatings that reduce the thrombogenicity related to blood-contacting medical devices, the benefits of these thrombogenicity-reducing coatings, and their limitations.

What Is Thrombogenicity?

Thrombogenicity refers to the tendency of a material or surface to induce the formation of blood clots, also known as thrombosis. In the context of medical devices that come into contact with blood, understanding and assessing thrombogenicity is crucial because excessive blood clot formation can lead to device failure and pose serious health risks to patients.

How Do Blood‐Contacting Medical Devices Initiate Thrombogenicity?

Blood-contacting medical devices, such as vascular grafts, stents, heart valves, and catheters, are often used to treat cardiovascular diseases. Thrombus (blood clot) formation is a common cause of failure of these devices. The clotting process initiated by these devices is complex and involves several interconnected steps:

• Protein Adsorption: When blood comes into contact with the artificial surface of a medical device, proteins in the blood plasma immediately start to adhere to it. This protein layer, which includes fibrinogen, fibronectin, and von Willebrand factor, plays a crucial role in the subsequent steps of clotting.

• Platelet Adhesion and Activation: Platelets, tiny disc-shaped cells in the blood, stick to the adsorbed proteins, particularly fibrinogen. Once attached, the platelets become activated and release substances that attract other platelets and activate the clotting cascade.

• Activation of the Coagulation Cascade: The coagulation cascade is a series of enzymatic reactions that lead to the formation of fibrin, a mesh-like protein that traps red blood cells and forms a clot. There are two main pathways in the coagulation cascade: the intrinsic pathway and the extrinsic pathway. Blood-contacting medical devices primarily activate the intrinsic pathway, which involves the activation of clotting factors XII, XI, IX, X, and finally, thrombin.

• Fibrin Formation and Clot Stabilization: Thrombin cleaves fibrinogen into fibrin monomers, which then polymerize into a fibrin mesh. This mesh traps red blood cells and platelets, forming a stable clot. Thrombus formation can potentially cause device failure. Thrombus fragments may detach and travel through the circulation, which can cause life-threatening complications like stroke and heart attack.

What Coatings Reduce Thrombogenicity in Medical Devices?

Thrombogenicity-reducing coatings represent a proactive approach to address the issues associated with clot formation on medical devices. These coatings are designed to modify the device's surface properties, creating an environment that minimizes the activation of clotting mechanisms and enhances compatibility with the body's circulatory system.

1. Polyzene-F Coating:

• Polyzene-F is an ultra-pure, high molecular poly(bis(trifluoroethoxy) phosphazene (PTFEP) coating.

• It has hydrophobic properties and has been used in cardiac stents that reduce thrombogenicity rates.

• The coating demonstrated anti-thrombogenic properties and reduced restenosis rate in several studies.

• Polyzene-F is among the promising anti-thrombotic coatings for cardiac stents.

2. PC Coating (Shield): It is a promising option for reducing thrombogenicity in medical devices. PC (phosphorylcholine) is naturally present in the cell membrane of red blood cells and is known to reduce the thrombogenicity of stents. PC derived from red blood cells is used as a coating on a pipeline embolization device (PED) that is not detected as foreign bodies by platelets. It reduces protein adsorption and thrombin generation, potentially lowering thrombogenicity. It has the potential to improve patient outcomes by minimizing blood clotting and inflammation and potentially reducing the need for DAPT(dual antiplatelet therapy).

3. Hydrophilic Coating:

• pHPC (phoenix) hydrophilic coatings are thin layers applied to the surface of medical devices to make them water-loving. This mimics the natural hydrophilic nature of blood vessels and tissues, promoting smoother interaction with blood and reducing the risk of unwanted adhesion of blood components like platelets and fibrin. Thus reducing thrombogenicity.

• pHPC is a glycan-based hydrophilic multilayer polymer coating, approximately 10 nm thin, that can be applied to nitinol surfaces, which are often used in the construction of medical devices like neurovascular stents.

• It stimulates the biological properties of the glycocalyx. The glycocalyx is a protective layer found on the luminal surface of the endothelium (inner lining of blood vessels); it prevents protein, platelet, and leukocyte adhesion to the endothelium.

4. Heparin Coating: Heparin is an anticoagulant, and coatings with heparin aim to reduce blood clot formation on the device's surface. However, the effectiveness of heparin coatings has shown inconsistency in different studies.

5. Other Coatings: Bivalirudin, dopamine-immobilized heparin, heparin-loaded graphene oxide on titanium surface, combined chondroitin 6-sulfate and heparin, albumin, and polyurethane have all shown promise in reducing platelet adhesion.

What Are the Benefits of Thrombogenicity-Reducing Coating?

• Reduced Risk of Blood Clots: This translates to improved patient outcomes and fewer re-intervention procedures.

• Enhanced Device Performance: Longer device lifespan and improved biocompatibility contribute to better therapeutic success.

• Reducing the Need for DAPT(Dual Antiplatelet Therapy): In some cases, thrombogenicity-reducing coatings may reduce the reliance on systemic anticoagulant medications. This is particularly important for patients who may be at risk of bleeding complications associated with anticoagulant therapy.

• Improved Patient Outcomes: Ultimately, the use of thrombogenicity-reducing coatings on medical devices aims to improve patient outcomes by lowering the incidence of complications related to thrombosis.

What Are the Limitations of Thrombogenicity-Reducing Coatings?

While thrombogenicity-reducing coatings show promise in enhancing the biocompatibility of blood-contacting medical devices, there are some limitations to consider:

• Many coatings, while effective initially, lose their antithrombotic properties over time.

• Different devices experience varying flow patterns and shear forces, which can impact the durability and effectiveness of coatings.

• Coatings that rely on drug delivery for antithrombotic effects face challenges in long-term protection against thrombosis.

• There is a lack of standardized methods to determine the thrombogenicity of medical device materials and assess the durability and longevity of coatings.

Conclusion

Thrombogenicity remains a significant challenge in the development of blood-contacting medical devices. Thrombogenicity-reducing coatings represent a promising avenue for mitigating this risk and improving the safety and efficacy of these devices. Ongoing research and advancements in materials science will play a crucial role in addressing the limitations of these coatings, ultimately leading to more reliable and biocompatible solutions for a wide range of medical applications.