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Ultrasoft microgels displaying emergent platelet-like behaviours

Nature Materials volume 13, pages 1108–1114 (2014)Cite this article

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Abstract

Efforts to create platelet-like structures for the augmentation of haemostasis have focused solely on recapitulating aspects of platelet adhesion1; more complex platelet behaviours such as clot contraction2 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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Figure 1: PLP design and characterization.
Figure 2: PLPs induce clotting in vitro.
Figure 3: PLPs induce clot collapse in vitro.
Figure 4: PLPs decrease bleeding time in vivo, and home to site of injury.

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Acknowledgements

The authors wish to thank L. Tucker and S. Pitrowski Lees for assistance with in vivo studies, A. Winburn for assistance with particle synthesis, Z. Meng for AFM images of ULC μgels films, and Y. Sakuri, Y. Qui and D. Myers for assistance with platelet-poor plasma isolation. Funding sources: NIH (HHSN268201000043C, R21EB013743 and R01EB011566), John and Mary Brock Discovery Research Fund, and DoD (W81XWH1110306) to T.H.B.; NIH (R21EB013743) and DoD (W81XWH1110306) to L.A.L.; American Heart Association Postdoctoral Fellowship to A.C.B.; NSF GRF to V.S.; NSF CAREER Award (DMR-1255288) to A.A.; NIH (R01HL121264, U54 HL11230 and NSF CAREER Award (1150235) to W.A.L.

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Author notes

  1. Ashley C. Brown and Sarah E. Stabenfeldt: These authors contributed equally to this work.

Authors and Affiliations

  1. The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia 30332, USA

    Ashley C. Brown, Byungwook Ahn, Riley T. Hannan, Victoria Stefanelli, Wilbur A. Lam & Thomas H. Barker

  2. School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, USA

    Ashley C. Brown, Kabir S. Dhada, Emily S. Herman & L. Andrew Lyon

  3. School of Biological and Health Systems Engineering, Arizona State University, Tempe, Arizona 85287, USA

    Sarah E. Stabenfeldt

  4. 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, Georgia 30322, USA

    Byungwook Ahn & Wilbur A. Lam

  5. Department of Pediatrics, Division of Pediatric Cardiology, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia 30322, USA

    Nina Guzzetta

  6. The George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA

    Alexander Alexeev

  7. The Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, Georgia 30332, USA

    Wilbur A. Lam, L. Andrew Lyon & Thomas H. Barker

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Contributions

A.C.B., S.E.S. and B.A., experimental design, data analysis and manuscript; R.T.H., K.S.D., E.S.H. and V.S., experimental design and data analysis; A.A., simulations, data analysis and manuscript; N.G., W.A.L., L.A.L. and T.H.B., experimental design and manuscript.

Corresponding authors

Correspondence to L. Andrew Lyon or Thomas H. Barker.

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The authors declare no competing financial interests.

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Brown, A., Stabenfeldt, S., Ahn, B. et al. Ultrasoft microgels displaying emergent platelet-like behaviours. Nature Mater 13, 1108–1114 (2014). https://doi.org/10.1038/nmat4066

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