Nonspherical ultrasound microbubbles

Proceedings of the National Academy of Sciences, vol. 120, pp. e2218847120

Abstract

Surface tension provides microbubbles (MB) with a perfect spherical shape. Here, we demonstrate that MB can be engineered to be nonspherical, endowing them with unique features for biomedical applications. Anisotropic MB were generated via one-dimensionally stretching spherical poly(butyl cyanoacrylate) MB above their glass transition temperature. Compared to their spherical counterparts, nonspherical polymeric MB displayed superior performance in multiple ways, including i) increased margination behavior in blood vessel-like flow chambers, ii) reduced macrophage uptake in vitro, iii) prolonged circulation time in vivo, and iv) enhanced blood-brain barrier (BBB) permeation in vivo upon combination with transcranial focused ultrasound (FUS). Our studies identify shape as a design parameter in the MB landscape, and they provide a rational and robust framework for further exploring the application of anisotropic MB for ultrasound-enhanced drug delivery and imaging applications.

Authors 26

1. Anshuman Dasgupta Aachen Institute for Experimental Molecular Imaging Medical Faculty

   Harvard University · Wyss Institute for Biologically Inspired Engineering · RWTH Aachen University

   Affiliation as printed

   Institute for Experimental Molecular Imaging, Medical Faculty, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany

   John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138

   Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115

2. Tao Sun

   Brigham and Women's Hospital · Harvard University · Wyss Institute for Biologically Inspired Engineering

   Affiliation as printed

   Focused Ultrasound Laboratory, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115

   John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138

   Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115

3. Roberto Palomba

   Italian Institute of Technology

   Affiliation as printed

   Laboratory of Nanotechnology for Precision Medicine, Istituto Italiano di Tecnologia, 16163 Genova, Italy

4. Elena Rama Aachen Institute for Experimental Molecular Imaging Medical Faculty

   RWTH Aachen University

   Affiliation as printed

   Institute for Experimental Molecular Imaging, Medical Faculty, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany

5. Yongzhi Zhang

   Brigham and Women's Hospital · Harvard University

   Affiliation as printed

   Focused Ultrasound Laboratory, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115

6. Chanikarn Power

   Brigham and Women's Hospital · Harvard University

   Affiliation as printed

   Focused Ultrasound Laboratory, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115

7. Diana Moeckel Aachen Institute for Experimental Molecular Imaging Medical Faculty

   RWTH Aachen University

   Affiliation as printed

   Institute for Experimental Molecular Imaging, Medical Faculty, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany

8. Mengjiao Liu Aachen Institute for Experimental Molecular Imaging Medical Faculty

   RWTH Aachen University

   Affiliation as printed

   Institute for Experimental Molecular Imaging, Medical Faculty, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany

9. Apoorva Sarode

   Harvard University

   Affiliation as printed

   John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138

10. Marek Weiler Aachen Institute for Experimental Molecular Imaging Medical Faculty

    RWTH Aachen University

    Affiliation as printed

    Institute for Experimental Molecular Imaging, Medical Faculty, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany

11. Alessandro Motta Aachen Institute for Experimental Molecular Imaging Medical Faculty

    RWTH Aachen University

    Affiliation as printed

    Institute for Experimental Molecular Imaging, Medical Faculty, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany

12. Céline Porte Aachen Institute for Experimental Molecular Imaging Medical Faculty

    RWTH Aachen University

    Affiliation as printed

    Institute for Experimental Molecular Imaging, Medical Faculty, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany

13. Zuzanna Magnuska Aachen Institute for Experimental Molecular Imaging Medical Faculty

    RWTH Aachen University

    Affiliation as printed

    Institute for Experimental Molecular Imaging, Medical Faculty, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany

14. Asmaa Said Elshafei Aachen Institute for Experimental Molecular Imaging Medical Faculty

    RWTH Aachen University

    Affiliation as printed

    Institute for Experimental Molecular Imaging, Medical Faculty, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany

15. Roman A. Barmin Aachen Institute for Experimental Molecular Imaging Medical Faculty

    RWTH Aachen University

    Affiliation as printed

    Institute for Experimental Molecular Imaging, Medical Faculty, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany

16. Adam Graham

    Harvard University

    Affiliation as printed

    John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138

17. Arthur McClelland

    Harvard University

    Affiliation as printed

    John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138

18. Dirk Rommel Aachen DWI - Leibniz Institute for Interactive Materials Institute of Technical and Macromolecular Chemistry

    DWI – Leibniz Institute for Interactive Materials · RWTH Aachen University

    Affiliation as printed

    DWI−Leibniz Institute for Interactive Materials, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany

    Institute of Technical and Macromolecular Chemistry, Polymeric Biomaterials, Rheinisch-Westfälische Technische Hochschule University Aachen, 52074 Aachen, Germany

19. Elmar Stickeler Aachen Department of Obstetrics and Gynecology Medical Faculty

    RWTH Aachen University

    Affiliation as printed

    Department of Obstetrics and Gynecology, Medical Faculty, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany

20. Fabian M. Kiessling Aachen Institute for Experimental Molecular Imaging Medical Faculty

    RWTH Aachen University

    Affiliation as printed

    Institute for Experimental Molecular Imaging, Medical Faculty, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany

21. Roger M. Pallares Aachen Institute for Experimental Molecular Imaging Medical Faculty

    RWTH Aachen University

    Affiliation as printed

    Institute for Experimental Molecular Imaging, Medical Faculty, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany

22. Laura De Laporte Aachen Advanced Materials for Biomedicine Institute of Applied Medical Engineering Medical Faculty DWI - Leibniz Institute for Interactive Materials Institute of Technical and Macromolecular Chemistry

    DWI – Leibniz Institute for Interactive Materials · RWTH Aachen University

    Affiliation as printed

    Advanced Materials for Biomedicine, Institute of Applied Medical Engineering, Medical Faculty, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany

    DWI−Leibniz Institute for Interactive Materials, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany

    Institute of Technical and Macromolecular Chemistry, Polymeric Biomaterials, Rheinisch-Westfälische Technische Hochschule University Aachen, 52074 Aachen, Germany

23. Paolo Decuzzi

    Italian Institute of Technology

    Affiliation as printed

    Laboratory of Nanotechnology for Precision Medicine, Istituto Italiano di Tecnologia, 16163 Genova, Italy

24. Nathan Judson McDannold

    Brigham and Women's Hospital · Harvard University

    Affiliation as printed

    Focused Ultrasound Laboratory, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115

25. Samir Mitragotri

    Harvard University · Wyss Institute for Biologically Inspired Engineering

    Affiliation as printed

    John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138

    Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115

26. Twan Lammers Aachen Institute for Experimental Molecular Imaging Medical Faculty

    RWTH Aachen University

    Affiliation as printed

    Institute for Experimental Molecular Imaging, Medical Faculty, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany