Efforts to create platelet-like structures for the augmentation of haemostasis have focused solely on recapitulating aspects of platelet adhesion; more complex platelet behaviours such as clot contraction are assumed to be inaccessible to synthetic systems. Here, we report the creation of fully synthetic platelet-like particles (PLPs) that augment clotting in vitro under physiological flow conditions and achieve wound-triggered haemostasis and decreased bleeding times in vivo in a traumatic injury model. PLPs were synthesized by combining highly deformable microgel particles with molecular-recognition motifs identified through directed evolution. In vitro and in silico analyses demonstrate that PLPs actively collapse fibrin networks, an emergent behaviour that mimics in vivo clot contraction. Mechanistically, clot collapse is intimately linked to the unique deformability and affinity of PLPs for fibrin fibres, as evidenced by dissipative particle dynamics simulations. Our findings should inform the future design of a broader class of dynamic, biosynthetic composite materials.
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http://dx.doi.org/10.1038/nmat4066 | DOI Listing |
Background: Germline haplodeficiency (RHD) is associated with thrombocytopenia, platelet dysfunction and predisposition to myeloid malignancies. Platelet expression profiling of a RHD patient showed decreased encoding for the A subunit of factor XIII, a transglutaminase that cross-links fibrin and induces clot stabilization. FXIII-A is synthesized by hematopoietic cells, megakaryocytes and monocytes.
View Article and Find Full Text PDFbioRxiv
November 2024
Department of Pediatrics, University of Michigan, Ann Arbor, MI.
Venous thrombosis is a well-known complication of sex hormone therapy, with onset typically within weeks to months after initiation. Worldwide, more than 100 million pre-menopausal women use combined oral contraceptives, with tens to hundreds of thousands developing thrombosis annually, resulting in significant morbidity and mortality. Although it is known that estrogens can alter expression of coagulation factors, the pathways and mechanisms that connect the two systems, as well as the proteins involved in progression to thrombosis, are poorly understood.
View Article and Find Full Text PDFJ Thromb Haemost
November 2024
Department of Physics, East Carolina University, Greenville, North Carolina, USA. Electronic address:
Fibrinogen and its insoluble degradation product fibrin are pivotal plasma proteins that play important roles in blood coagulation, wound healing, and immune responses. This review highlights research from the last 24 months connecting our progressing view of fibrin(ogen)'s structure, and in particular its conformational flexibility and posttranslational modifications, to its (patho)physiologic roles, molecular interactions, mechanical properties, use as a biomaterial, and potential as a therapeutic target. Recent work suggests that fibrinogen structure is highly dynamic, sampling multiple conformations, which may explain its myriad physiologic functions and the presence of cryptic binding sites.
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