Quantifying Interactions Between Nanoengineered Particles and Cells
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Quantifying Interactions Between Nanoengineered Particles and Cells Matthew William Faria ORCID: 0000-0003-1729-5813 Doctor of Philosophy January 2018 Department of Biomedical Engineering and Department of Chemical Engineering, The University of Melbourne Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy 1 Abstract Nanoengineering has recently emerged as a promising technology for the understanding, treatment, and diagnosis of disease. One of its most compelling potential uses is in the design of particles with controlled interactions with particular cell types. Significant research effort has been devoted to developing particles that exhibit a variety of interesting behaviors, including stealth, targeting, cargo carrying capabilities, or responsiveness to biological environments. In vitro experiments with cultured cells are fundamental to understanding and studying the interface between nanoengineered particles and biological systems. However, partially due to the wide range of physicochemical properties nanomaterials exhibit, quantification and generalization of data from in vitro bio-nano experiments has unique challenges when compared to traditional small-molecule drugs or materials in bulk. As the fields of bio-nano research and nanomedicine have matured, in vitro quantification has become a significant barrier to understanding, characterizing, and comparing newly developed particle systems. This thesis addresses three interrelated areas that are necessary to accurately quantify in vitro interactions between nanoengineered particles and cells. First, particle-dependent variation between the amount of material administered and that which reaches the surface of cells (in vitro dosimetry) is studied. Second, instrument independent quantification of cell-particle association is used to study differences in association induced by labeling and cytometry technique. Third, a theoretical framework to isolate the biological kinetics of association is developed, and is used to compare cell-particle association results from experiments varying in particle type and cell line. Though the primary focus of this thesis is computational, a mixture of experimental, mathematical, and computational strategies are utilized. 2 Declaration This is to certify that: (i) The thesis comprises only my original work towards the degree of Doctor of Philosophy (PhD) except where indicated in the Preface; (ii) Due acknowledgement has been made in the text to all other material used; (iii) The thesis is less than 100,000 words in length, exclusive of tables, bibliographies, and appendices. Matthew Faria 3 Preface Statement of author contributions The content in Chapter 2 was previously published as a part of “A Framework to Account for Sedimentation and Diffusion in Particle–Cell Interactions” (in which the candidate was a co-first author); and “Dynamic Flow Impacts Cell–Particle Interactions: Sedimentation and Particle Shape Effects” (in which the candidate was a co-author). Full details of these manuscripts are included below. Within this chapter, particle synthesis, particle characterization, 3D printing, cell experiments, some figure preparation, and aluminum machining were performed by other authors or technicians. The manuscript “A Framework to Account for Sedimentation and Diffusion in Particle–Cell Interactions” is included as Appendix A, and this appendix is referenced for work that needs to be introduced within Chapter 2, but in which the candidate had a small role. In other cases (i.e., the candidate performed the research, as well as writing and revising relevant sections of the manuscript), the accompanying section is included verbatim within this chapter. In Chapter 3, PMA particles were prepared by Dr. Danzi Song. Zwitterionic particles were prepared by Dr. Alessia Weiss. Mass cytometry was performed by Dr. Andrew John Mitchell. EDX mapping was performed by Dr. Nadja Bertleff-Zieschang. Cell incubation experiments in the section Attenuation of Gd-DOTA signal in biological environments were designed and performed by Ms. Kellen Lowrie. The content in Chapter 4 has been prepared for submission as a scientific manuscript, in which the candidate is a first author, and co-authors are: Ka Fung Noi, Mattias Björnmalm, Yi Ju, Frank Caruso, and Edmund Crampin. Other authors contributions were provision and discussion of data; 4 to discuss, refine, and challenge ideas; to suggest and verify some of the mathematical modeling developed; and manuscript revision after the preparation of an initial draft. The content in Chapter 5 has been prepared for submission as a scientific manuscript, in which the candidate is a first author, and co-authors are: Mattias Björnmalm, Kristofer J Thurecht, Stephen J Kent, Robert G Parton, Maria Kavallaris, Angus PR Johnston, J Justin Gooding, Simon R Corrie, Ben J Boyd, Pall Thordarson, Andrew K Whittaker, Molly M. Stevens, Clive A Prestidge, Christopher JH Porter, Wolfgang J Parak, Thomas P Davis, Edmund Crampin,, and Frank Caruso. Other authors contributions were to discuss components of the proposed standard (including inclusion and removal of additional components), manuscript revision after the preparation of an initial draft, and preparation of the companion checklist. The illustration in this chapter was prepared by Amino Creative, LLC. For the purposes of readability and consistency with other scientific writing, the plural tense (“we did”) is used within this thesis, rather than the passive voice or singular tense (“I did”). No work within this thesis was completed prior to enrolment in the degree, nor was any work submitted for other qualifications. Permissions Chapter 2 is adapted with permission from two previously published manuscripts: Cui, J., Faria, M., Björnmalm, M., Ju, Y., Suma, T., Gunawan, S.T., Richardson, J.J., Heidari, H., Bals, S., Crampin, E.J. and Caruso, F., 2016. A Framework to Account for Sedimentation and Diffusion in Particle–Cell Interactions. Langmuir, 32(47), pp.12394-12402; and Björnmalm, M., Faria, M., 5 Chen, X., Cui, J. and Caruso, F., 2016. Dynamic Flow Impacts Cell–Particle Interactions: Sedimentation and Particle Shape Effects. Langmuir, 32(42), pp.10995-11001. Copyright 2016 American Chemical Society. Appendix A is reprinted with permission from Cui, J., Faria, M., Björnmalm, M., Ju, Y., Suma, T., Gunawan, S.T., Richardson, J.J., Heidari, H., Bals, S., Crampin, E.J. and Caruso, F., 2016. A Framework to Account for Sedimentation and Diffusion in Particle–Cell Interactions. Langmuir, 32(47), pp.12394-12402. Copyright 2016 American Chemical Society." Funding The candidate was funded through a NICTA/Data61 scholarship for the duration of his candidature. Publications The following publications were produced over the course of this candidature. Candidate’s name is shown in bold, and publications are listed in rough order of contribution: • Cui, J.*, Faria, M.*, Björnmalm, M., Ju, Y., Suma, T., Gunawan, S.T., Richardson, J.J., Heidari, H., Bals, S., Crampin, E.J. and Caruso, F., 2016. A Framework to Account for Sedimentation and Diffusion in Particle–Cell Interactions. Langmuir, 32(47), pp.12394- 12402. * indicates co-first authorship. • Björnmalm, M., Faria, M. and Caruso, F., 2016. Increasing the impact of materials in and beyond bio-nano science. J. Am. Chem. Soc, 138(41), pp.13449-13456. 6 • Björnmalm, M., Faria, M., Chen, X., Cui, J. and Caruso, F., 2016. Dynamic Flow Impacts Cell–Particle Interactions: Sedimentation and Particle Shape Effects. Langmuir, 32(42), pp.10995-11001. • Björnmalm, M., Faria, M. and Caruso F., 2016. Advancing Research Using Action Cameras. Chem. Mater. 28(23), pp.8441–8442. • Cui, J., Richardson, J.J., Björnmalm, M., Faria, M. and Caruso, F., 2016. Nanoengineered templated polymer particles: Navigating the biological realm. Accounts of chemical research, 49(6), pp.1139-1148. • Björnmalm, M., Cui, J., Bertleff-Zieschang, N., Song, D., Faria, M., Rahim, M.A. and Caruso, F., 2016. Nanoengineering Particles through Template Assembly. Chemistry of Materials, 29(1), pp.289-306. • Rahim, M., Björnmalm, M., Suma, T., Faria, M., Ju, Y., Kempe, K., Müllner, M., Ejima, H., Stickland, A.D. and Caruso, F., 2016. Metal–Phenolic Supramolecular Gelation. Angewandte Chemie International Edition, 55(44), pp.13803-13807. • Richardson, J.J., Liang, K., Lisi, F., Björnmalm, M., Faria, M., Guo, J. and Falcaro, P., 2016. Controlling the Growth of Metal‐Organic Frameworks Using Different Gravitational Forces. European Journal of Inorganic Chemistry, 2016(27), pp.4499-4504. • Rahim, M., Björnmalm, M., Bertleff‐Zieschang, N., Besford, Q., Mettu, S., Suma, T., Faria, M. and Caruso, F., 2017. Rust‐Mediated Continuous Assembly of Metal– Phenolic Networks. Advanced Materials, 29(22). Oral presentations A selection of oral presentations delivered during this candidature are listed below: 7 • Faria, M. “Quantifying nanoparticle-cell interactions in vitro”, University of New South Wales, November 2017 • Faria, M. “Quantifying bio-nano interactions: a computational approach”, The University of Melbourne, August 2017 • Faria, M., Björnmalm, M. “Increasing the Impact of Materials in and beyond Bio-Nano Science”, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, March 2017 • Faria, M., “A quantitative metric of nanoparticle targeting in vitro”, CBNS 2016 Research Workshop, Novotel Barossa Valley, December 2016 • Faria, M. “Computational approaches to nano-bio interactions”, Peter Doherty Institute for Infection