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Multivalent Programmable Interactions Between Lipid Vesicles: Towards Responsive Soft Materials 10.17863/CAM.51277 Amjad, Omar Cicuta, Pietro Di Michele, Lorenzo Lipid membranes and lipid vesicles have been studied extensively in the last 50 years in order to characterise their biological, chemical and physical properties. Such work is of interest from a fundamental biological perspective, but also due to the applications that their biocompatibility affords: in biotechnological, pharmaceutical, food science and cosmetic applications. From this work, it is clear that lipid membranes display a large number of remarkable traits: they can form a wide range of sizes and morphologies, are deformable and can be functionalised with a variety of structures. More recently, multivalent interactions have been exploited to drive self-assembly of nanoparticles, hard colloids and compliant units including emulsion droplets and lipid vesicles. By applying this to deformable lipid vesicles, formation of links between two membranes produces morphological changes unachievable in hard colloidal systems, and the liquid interface of liquid-phase bilayers allows for the diffusion of the multivalent constructs across the membrane of the lipid vesicle. Against this background of membrane science and multivalent interactions, this thesis develops new experimental approaches to exploit these extra degrees of freedom to develop novel lipid-based soft responsive materials with potential ’real-world’ applications, such as in molecular sensing. In Chapter 1, the motivations for this work are introduced, before introducing the requisite background literature and general experimental techniques in Chapters 2 and 3 respectively. In Chapter 4 we show a system of single lipid vesicles adhering to a flat supported lipid bilayer through multimeric multivalent interactions, which we study to characterise the morphological and mechanical changes of the vesicles in response to external ligands. We show that the mechanical properties of the vesicles, in particular their membrane tension, change dramatically on adhesion, and that the number of adhering vesicles is dependent on the concentration of the external ligand due to combinatorial entropy, which we confirm through consideration of a simple statistical mechanical model. In Chapter 5 we use Differential Dynamic Microscopy to study the dynamics of a thermoreversible gel consisting of diffusive attractive soft colloids (large unimlamellar vesicles functionalised with complementary DNA constructs), and fit the dynamics with a stretched/compressed exponential model. From the fit parameters, we observe differing levels of spatial heterogeniety of the dynamics of the sample within different regimes below, above and around the gel/melting points, as well as differing length scales of the dynamics, which differ between quenching and melting experiments. From the statics and dynamics, we see evidence for multiple phenomena, including coarsening as well as ballistic events corresponding to strand breakages. In Chapter 6 we propose a method for high-throughput vesicle production. We characterise the method and the vesicles produced, as well as demonstrating novel applications, most notably the high-throughput production of vesicles encapsulating responsive DNA circuitry, highlighting the potential of this method in bottom-up synthetic biology and the design of programmable materials. Furthermore, we demonstrate the possibility of on-chip functionalisation of membrane constructs into the lipid membranes, in this case cholesterol anchored DNA constructs. In Chapter 7 we study dense packings of vesicles assembled using multivalent complementary DNA interactions, through passive tracking of diffusive colloidal particles and active microrheology using magnetic tweezers. We observe changes in the structure in response to increased temperature, DNA concentration and aging leading to reduced pore sizes. From a rheological standpoint, we observe strain hardening of the material through repeated creep tests, with the ability to reset the material by increasing the temperature above the melting point of the system. The material stiffens and becomes more viscous, which we observe through the application of a constitutive and fractional rheological model respectively. In this thesis we demonstrate the responsiveness of these multivalent construct functionalised lipid vesicle based soft materials by showing the ability to tune the structure, rheology and dynamics of such materials, as well as proposing a method for high throughput, monodisperse production of functionalised lipid vesicles. These results lead to further potential avenues of research, and demonstrate suitability for and preliminary steps towards applications of these responsive materials in fields such as molecular sensing. University of Cambridge 2019-07-02 Thesis Doctoral Doctor of Philosophy (PhD) en EPSRC CDT for Sensor Technologies and Applications https://www.repository.cam.ac.uk/handle/1810/304193 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/e938415a-e3e8-4c4b-8a02-03e898e432a2/download 91e11e58ed67a76a5112d959fdd41567 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/89146635-c50d-4427-b18e-9527b9389ae5/download 87eda9de84448d1f82354d60eee3eb5f https://www.rioxx.net/licenses/all-rights-reserved/ Lipid Interfaces Lipid Membranes Lipid Vesicles Liposomes Ligand-Receptor Interactions DNA-mediated Interactions Programmable Materials Responsive Materials Adhesion Gels Soft Matter Self-Assembly Rheology Magnetic-Tweezers Differential Dynamic Microscopy Microfluidics Microfluidics for Lipid Vesicle Production Sensing