Blueprinting Self-Assembled Soft Matter: An `Easy' Approach to Advanced Material Synthesis in Drug Delivery and Wound Healing
Dowling, Matthew Burke
Raghavan, Srinivasa R
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From Jello to mayonnaise to silly putty to biological cells, our world is replete with "soft matter" - materials that behave as soft, deformable solids or highly viscoelastic liquids. Living systems, in particular, can be thought of as extremely sophisticated `soft' machines, with each cellular unit representing a touchstone for the functional potential of soft materials built via self-assembly. Drawing inspiration from biology, we blueprint soft biomaterial designs which rely upon self-assembly to achieve enhanced functionality. As opposed to complex synthesis schemes often used to develop improved biomaterials, we take an `easy' approach by allowing relatively simple molecules orchestrate themselves into advanced machines. In this dissertation, we describe four separate "soft" systems, all constructed by self-assembly of amphiphilic molecules under designed and/or triggered conditions in aqueous media. These systems revolve around a common theme: the structural tandem of (1) vesicles and (2) biopolymers, and the resulting interactions between the two. Our blueprints show promise in several important biomedical applications including controlled drug release, tissue engineering, and wound care. In the first part of this study, we blueprint a biopolymer gel that entraps pH-sensitive vesicles. The vesicles are formed by the self-assembly of a single-tailed fatty acid surfactant. We show that the gel has pH-responsive properties imparted upon it via the embedded vesicle nanostructures. Specifically, when the gel is brought in contact with a high pH buffer, the diffusion of buffer into the gel disrupts the vesicles and transforms them into micelles. Accordingly, a vesicle-micelle front moves through the gel, and this can be visually seen by a difference in color. The disruption of vesicles means that their encapsulated solutes are released into the bulk gel, and in turn these solutes can rapidly diffuse out of the gel. Thus, we can use pH to tune the release rate of model drug molecules from these vesicle-loaded gels into the external solution. In the second part, we have blueprinted hybrid biopolymer capsules containing drug-loaded vesicles by means of a one-step self-assembly process. These capsules are called "motherships" as each unit features a larger container, the polymer capsule, carrying a payload of smaller vesicular containers, or "babyships," within its lumen. These motherships are self-assembled via electrostatic interactions between oppositely charged polymers/surfactants at the interface of the droplet. Capsule size is simply dictated by drop size, and capsules of sizes 200-5000 µm are produced here. Lipid vesicles, i.e. the babyships, are retained inside motherships due to the diffusional barrier created by the capsule shell. The added transport barrier provided by the vesicle bilayer in addition to the capsule shell provides sustained drug release from the motherships. Furthermore, this one-step drop method allows for the rapid synthesis of soft materials exhibiting structural features over a hierarchy of length scales, from nano-, to micro- to macro-. Thirdly, we have therapeutically functionalized biopolymer films by simply passing a solution of vesicles over the film surface. We deposit films of an associating biopolymer onto patterned solid substrates. Subsequently, these polymer films are able to spontaneously capture therapeutically-loaded vesicles from solution; this is demonstrated both for surfactant as well as lipid vesicles (liposomes). Importantly, it is verified that the vesicles are intact - this is shown both by direct visualization of captured vesicles (via optical and cryo-transmission electron microscopy) as well as through the capture and subsequent disruption of drug filled vesicles. Such therapeutically-functionalized films may be of use in the treatment of chronic wounds and burns. Lastly, we have demonstrated that the addition of a certain biopolymer transforms a suspension of whole blood into a gel. This blueprint is inspired from previous research in our group on the biopolymer-induced gelation of vesicles, which are structurally similar to cells. Upon mixture with heparinized human whole blood, this amphilic biopolymer rapidly forms into an "artificial clot." These mixtures have highly elastic character, with the mixtures able to hold their own weight upon vial inversion. Moreover, the biopolymer shows significant hemorrhage-controlling efficacy in animal injury models. Such biopolymer-cell gelation processes are shown to be reversed via introduction of an amphiphilic supramolecule, thus introducing the novel concept of the "revesible hemostat." Such a hemostatic functionality may be of large and unprecedented use in clinical the treatment of problematic hemorrhage both in trauma and routine surgeries.