ICAM-1-targeted thrombomodulin mitigates tissue factor-driven inflammatory thrombosis in a human endothelialized...

Area of Science:

• Biomedical Engineering
• Hematology
• Immunology

Background:

• Endothelial thrombomodulin (TM) loss causes inflammation, coagulation, and ischemia in various diseases.
• Existing animal models have limitations for testing humanized therapeutics due to biological differences.
• Targeted fusion proteins (scFv/TM) show promise for treating inflammatory thrombosis.

Purpose of the Study:

• To develop a human whole-blood microfluidic model for evaluating inflammatory thrombosis therapeutics.
• To compare a novel humanized ICAM-1 targeted scFv/TM biotherapeutic (hTM/R6.5) against existing antithrombotics.
• To assess the efficacy of hTM/R6.5 in a protein C-dependent manner.

Main Methods:

• Development of a multichannel microfluidic system simulating human whole-blood flow and inflammatory coagulation.
• Quantification of fibrin deposition, leukocyte, and platelet adhesion using real-time microscopy.
• Head-to-head comparison of hTM/R6.5 with soluble TM, anti-TF antibodies, and hirudin.

Main Results:

• The microfluidic model accurately replicated TF-driven coagulation and inflammatory responses.
• Targeted hTM/R6.5 demonstrated superior inhibition of coagulation compared to untargeted agents.
• hTM/R6.5 showed enhanced efficacy in a protein C-dependent manner and synergistic effects with supplemental PC.

Conclusions:

• The developed microfluidic system is a valuable platform for studying humanized therapeutics under flow.
• ICAM-1 targeted scFv/TM biotherapeutics hold significant translational potential for inflammatory thrombosis.
• This model facilitates rigorous preclinical evaluation of novel antithrombotic strategies.