Uncontrolled bleeding represents a significant clinical challenge in general surgery, trauma, and emergency medicine. Exsanguination (bleeding) is the major cause of death from traumatic injury (~ 40%) and bleeding following invasive surgeries such as cardiopulmonary bypass is associated with significant morbidity and mortality. During the normal clotting cascade, the protease thrombin is activated, which in turn activates dormant circulating platelets and the clotting protein precursor, fibrinogen. Activated platelets form a hemostatic plug at the site of injury, stemming blood loss. Platelets are sufficient to achieve short-term hemostasis and are critical to the maturation of stable fibrin-based clots via their activity in fibrin recruitment and clot contraction. Thus, it is not surprising that their massive dilution during hemorrhage or active inhibition during surgery results in a failure of the clotting system. Current hemostasis technologies include topical sealants, exothermic zeolites and recombinant clotting factors. Each of these approaches has demonstrated modest successes, yet all have significant drawbacks such as a lack of wound specificity; none are as ?evolved? as the natural wound-responsive hemostasis system. Thus, more recent efforts have focused on creation of synthetic analogs of platelets. The vital platelet functions that one would like to recapitulate include injury-triggered enhancement of fibrin clot formation and clot contraction/stabilization. To date, artificial platelet approaches only recapitulate clot/platelet binding in a non-triggered (i.e. constitutive) and non-specific fashion and lack the other critical platelet functions. Here we propose a novel and simple approach to the creation of platelet-like structures through the application of synthetic biology. We are proposing two aims.
The first aim i s to understand how our platelet-like particles interact with various stages of the coagulation cascade and to understand the fundamental mechanism of action of our platelet-like particles in augmenting hemostasis.
The second aim i s to explore the in vivo function of the platelet-like particles, specifically in the augmentation of hemostasis in multiple models of trauma-associated coagulopathy.

Public Health Relevance

Bleeding is the #1 cause of death due to trauma and represents a significant source of morbidity following surgery. In this application, we propose the development of an advanced, wound-responsive hemostasis system that can rescue certain platelet functions and augment hemostasis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Warren, Ronald Q
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Virginia
Biomedical Engineering
Schools of Engineering
United States
Zip Code
Zhang, Yun; Qiu, Yongzhi; Blanchard, Aaron T et al. (2018) Platelet integrins exhibit anisotropic mechanosensing and harness piconewton forces to mediate platelet aggregation. Proc Natl Acad Sci U S A 115:325-330
Mannino, Robert G; Pandian, Navaneeth Kr; Jain, Abhishek et al. (2018) Engineering ""Endothelialized"" Microfluidics for Investigating Vascular and Hematologic Processes Using Non-Traditional Fabrication Techniques. Curr Opin Biomed Eng 5:13-20
Sakurai, Yumiko; Hardy, Elaissa T; Ahn, Byungwook et al. (2018) A microengineered vascularized bleeding model that integrates the principal components of hemostasis. Nat Commun 9:509
Brockman, Joshua M; Blanchard, Aaron T; Pui-Yan Ma, Victor et al. (2018) Mapping the 3D orientation of piconewton integrin traction forces. Nat Methods 15:115-118
Welsch, Nicole; Brown, Ashley C; Barker, Thomas H et al. (2018) Enhancing clot properties through fibrin-specific self-cross-linked PEG side-chain microgels. Colloids Surf B Biointerfaces 166:89-97
Barker, Thomas H; Engler, Adam J (2017) The provisional matrix: setting the stage for tissue repair outcomes. Matrix Biol 60-61:1-4
Douglas, Alison M; Fragkopoulos, Alexandros A; Gaines, Michelle K et al. (2017) Dynamic assembly of ultrasoft colloidal networks enables cell invasion within restrictive fibrillar polymers. Proc Natl Acad Sci U S A 114:885-890
Welsch, Nicole; Lyon, L Andrew (2017) Oligo(ethylene glycol)-sidechain microgels prepared in absence of cross-linking agent: Polymerization, characterization and variation of particle deformability. PLoS One 12:e0181369
Nellenbach, Kimberly; Brown, Ashley C (2017) Peptide Mimetic Drugs for Modulating Thrombosis and Hemostasis. Drug Dev Res 78:236-244
Hansen, Caroline E; Myers, David R; Baldwin, W Hunter et al. (2017) Platelet-Microcapsule Hybrids Leverage Contractile Force for Targeted Delivery of Hemostatic Agents. ACS Nano 11:5579-5589

Showing the most recent 10 out of 13 publications