2. Academic Validation
  3. Clinically relevant clot resolution via a thromboinflammation-on-a-chip

Clinically relevant clot resolution via a thromboinflammation-on-a-chip

  • Nature. 2025 May;641(8065):1298-1308. doi: 10.1038/s41586-025-08804-7.
Yongzhi Qiu 1 2 3 4 5,  Jessica Lin 6 7 8 9 10,  Audrey Wang 6 7 8 9 10,  Zhou Fang 6 9,  Yumiko Sakurai 6 7 8 9 10,  Hyoann Choi 6 7 8 9 10,  Evelyn K Williams 6 7 8 9 10,  Elaissa T Hardy 6 7 8 9 10,  Kristin Maher 11,  Ahmet F Coskun 6 9,  Gary Woods 7,  Wilbur A Lam 12 13 14 15 16
Affiliations

Affiliations

  • 1 The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA, USA. yongzhi.qiu@emory.edu.
  • 2 Department of Pediatrics, Division of Pediatric Hematology/Oncology, Aflac Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA. yongzhi.qiu@emory.edu.
  • 3 Winship Cancer Institute of Emory University, Atlanta, GA, USA. yongzhi.qiu@emory.edu.
  • 4 Parker H. Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA. yongzhi.qiu@emory.edu.
  • 5 The Institute for Matter and Systems, Georgia Institute of Technology, Atlanta, GA, USA. yongzhi.qiu@emory.edu.
  • 6 The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA, USA.
  • 7 Department of Pediatrics, Division of Pediatric Hematology/Oncology, Aflac Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA.
  • 8 Winship Cancer Institute of Emory University, Atlanta, GA, USA.
  • 9 Parker H. Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA.
  • 10 The Institute for Matter and Systems, Georgia Institute of Technology, Atlanta, GA, USA.
  • 11 Division of Hematology, Oncology, Bone Marrow Transplant, and Cellular Therapy, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.
  • 12 The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA, USA. wilbur.lam@emory.edu.
  • 13 Department of Pediatrics, Division of Pediatric Hematology/Oncology, Aflac Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA. wilbur.lam@emory.edu.
  • 14 Winship Cancer Institute of Emory University, Atlanta, GA, USA. wilbur.lam@emory.edu.
  • 15 Parker H. Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA. wilbur.lam@emory.edu.
  • 16 The Institute for Matter and Systems, Georgia Institute of Technology, Atlanta, GA, USA. wilbur.lam@emory.edu.
PMID: 40175551 DOI: 10.1038/s41586-025-08804-7
Abstract

Thromboinflammation occurs in various diseases, leading to life-threatening microvascular occlusion with resulting end-organ failure1-4. Importantly, how microvascular thromboinflammation resolves remains poorly understood due to the small size-scale of microvasculature and the long duration (weeks to months) of this process. Here we introduce a hydrogel-based thromboinflammation-on-a-chip model with long-term culture capabilities to model microvascular thromboinflammation and monitor clot resolution over clinically and physiologically relevant timescales (up to months). Using this system, we mapped out the distinct temporal phases of clot resolution in microvascular thromboinflammation. Using multiplexed RNA fluorescence in situ hybridization in combination with our thromboinflammation-on-a-chip model, we observed that inflammation shifts the endothelium fibrinolytic balance to favour thrombosis and pinpointed neutrophil Elastase as a double-edged sword that induces clot resolution but also tissue damage. We then investigated the mechanisms of potential therapeutic agents that either prevent microvascular thrombosis or accelerate clot resolution. Specifically, we observed that, in thromboinflammation, (1) early tissue plasminogen activator administration within 3 h directly improves endothelial barrier function; (2) prophylactic defibrotide and enoxaparin suppress microvascular thromboinflammation through endothelium-mediated mechanisms; and (3) combining enoxaparin with crizanlizumab reduces microvascular occlusion and protects endothelial function in sickle cell disease. These data introduce a paradigm in investigating the underlying mechanisms of thromboinflammatory clot resolution and conducting drug discovery thereof.

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