Editors' ChoiceBIOMATERIALS

The Clot Thickens…

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Science Translational Medicine  03 Dec 2014:
Vol. 6, Issue 265, pp. 265ec206
DOI: 10.1126/scitranslmed.aaa3410

Blood loss is the primary cause of death in civilian and battlefield injuries. Current hemostatic technologies, including topical sealants and recombinant clotting factors, are only modestly effective and do not fully stem the flow of uncontrolled bleeding. Several researchers have attempted to engineer microscale particles that adhere to natural platelets in order to augment clot stability. However, these so-called “synthetic platelets” fail to recapitulate critical aspects of platelet behavior, such as homing to the site of injury, facilitation of clot contraction, and the wound specificity that prevents clotting outside of the wound area. To address these drawbacks, Brown, Stabenfeldt, and colleagues designed microgel particles that attach to and spread within a fibrin network that comprises a forming clot.

The team took advantage of a rare chain-transfer event that occurs spontaneously upon precipitation polymerization of N-isopropylacrylamide and acrylic acid to form ultra-low cross-linked gel particles of about 1 micron in diameter. Then, using a phage display screen, the researchers discovered a binding motif with high specificity for fibrin but very little for its soluble form, fibrinogen, which is ubiquitous in the blood. By attaching this motif to the microgels, the researchers conferred wound-area specificity to the “platelet-like particles” (PLPs) while simultaneously causing them to home to the site of injury. The PLPs caused contraction of clots in vitro that had similar structures to those contracted by platelets. Computer simulations and experiments with more highly cross-linked particles showed that this behavior was a result of both the PLPs’ high deformability and adhesiveness for fibrin, which allowed them to form bridges between adjacent strands of fibrin. The PLPs were able to augment clotting in blood from patients with an underdeveloped coagulation system but not in patients with severe hemophilia, which prevents them from forming fibrin—the PLPs trigger. When injected into rats prior to severe femoral vein injury, the PLPs caused a significant reduction in bleeding time compared to control microgels that did not have the ability to home to and bind fibrin.

These results are exciting, but it is important to note that the technology has not yet been tested in a realistic model of extreme bleeding, in which the PLPs are administered after an injury occurs. In addition, the PLPs were not able to cause clot contraction as quickly as native platelets and do not recapitulate other important aspects of activated platelets, such as their release of growth factors that stimulate wound healing. Nevertheless, this technology represents the first time that engineers were able to recapitulate multiple aspects of platelet behavior, with major consequences for emergency medicine.

A. C. Brown et al., Ultrasoft microgels displaying emergent platelet-like behaviours. Nat. Mater. 13, 1108–1114 (2014). [Abstract]

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