No description available.

No description available.

Thesis (Ph.D.)--Brown University, 2005. / Vita. Thesis advisor: Michael J. Lysaght. Includes bibliographical references (leaves 183-193). Also available online.

In this study the role of passive mechanism for deformation of neutrophils, namely the effect of mechanical properties, was studied using microgels as model system. Both alginate-poly(N-isopropylacrylamide) interpenetrating polymer network (IPN) microgels and agarose microgels were synthesized in microfluidic device. The Young’s modulus and relaxation time of the IPN microgels were studied using atomic force microscopy equipped with a tipless cantilever. The lower limits of the elasticity found in this study were within the range of the elasticity reported for neutrophils. Agarose microgels were also prepared with a range of elastic shear modulus similar to neutrophils, and their flow under constrained geometries was studied. The flow profiles of four agarose microgel samples in a microchannel containing a constriction were analyzed. It was found that the stiffness of the microgels affected their velocity before, in and after the constriction.

In this study the role of passive mechanism for deformation of neutrophils, namely the effect of mechanical properties, was studied using microgels as model system. Both alginate-poly(N-isopropylacrylamide) interpenetrating polymer network (IPN) microgels and agarose microgels were synthesized in microfluidic device. The Young’s modulus and relaxation time of the IPN microgels were studied using atomic force microscopy equipped with a tipless cantilever. The lower limits of the elasticity found in this study were within the range of the elasticity reported for neutrophils. Agarose microgels were also prepared with a range of elastic shear modulus similar to neutrophils, and their flow under constrained geometries was studied. The flow profiles of four agarose microgel samples in a microchannel containing a constriction were analyzed. It was found that the stiffness of the microgels affected their velocity before, in and after the constriction.

Thesis (M.E.)--University of Canterbury, 2008. / Typescript (photocopy). Includes bibliographical references (p. 121-125). Also available via the World Wide Web.

Over the last six decades, the field of drug delivery has advanced considerably, from sustained oral release technology to pH-responsive polymers. Innovation in the space has progressed alongside the development of new categories of drugs, as well as improvements in electronics and material science which have enabled new modalities of external stimulation. Nevertheless, the traditional challenges of drug delivery persist, including the need to reduce off-target toxicity, minimize invasiveness of administration, and bypass biological barriers; these challenges are particularly apparent for drug delivery applications in difficult-to-reach areas of the body, such as tumors or areas beyond the blood-brain barrier. Furthermore, as therapeutics become more targeted, the need for corresponding delivery methods becomes even more vital to ensure treatment effectiveness with minimal side effects. In this dissertation, we aim to demonstrate a new strategy for on-demand and localized drug delivery which is easy to fabricate and delivers a large payload relative to device size, is responsive to external stimulation for triggered release, and can be integrated into a system for real-time actuation during a physiological process. In Aim 1, we developed a microfluidic fabrication technique for making biphasic microcapsules loaded with model drug. This method relied on microfluidic droplet methods, with sufficient interfacial tension between two on-chip phases to cause droplet formation. Typically, these systems rely on an aqueous-oil interface for sufficient interfacial tension; to fabricate a biocompatible microcapsule, we formed biphasic microcapsules composed of an aqueous-based inner and outer phase, without an oil intermediate phase, with aqueous two-phase system properties. Additionally, we incorporated on-chip photopolymerization, designing the microfluidic chip and light source to minimize refracted ultraviolet exposure. The resulting drug-loaded microcapsules were stable, with minimal background leakage. This fabrication technique can produce a high-throughput supply of monodisperse microcapsules, which can be modified for a variety of therapeutic payloads and easily injected in targeted region in the body. In Aim 2, we adapted these drug-loaded microcapsules for ultrasound-triggered release. Focused ultrasound (FUS) is a minimally-invasive method of stimulating release from a device, which can penetrate deep within the body and is compatible with a variety of materials; when applied at sufficient intensity and duration, it can induce heating, cavitation, or both. We tuned the applied ultrasound parameters to minimize temperature increases in surrounding tissue phantoms, while inducing step-like release profiles from the microcapsules over the course of multiple cycles of pulsed FUS. Under these applied conditions, we detected acoustic signatures consistent with inertial cavitation and visually observed structural breakdown of the microcapsules corresponding to cavitation-related effects. This release strategy is highly targeted, inducing drug release from microcapsules within a narrow focal area with minimal risk to surrounding tissue. Finally, in Aim 3, we performed in vitro demonstrations of drug-loaded actuators, as initial demonstrations towards a system of integrated sensors, actuators, and adaptive learning algorithms for closed-loop control over physiological processes involved in wound healing. We experimented with both the aforementioned microcapsules and with a liposome-loaded scaffold as drug-loaded actuators, and tested both actuators with three ultrasound transducers which offered a range of portability, intensity ranges, and imaging capacities. Next, we developed in vitro testing setups incorporating the actuators with either a cell monolayer or a three-dimensional cell construct, mimicking a wound site, and validated ultrasound-triggered drug-release with minimal cell damage. To demonstrate cell uptake of the released therapeutic agents, we modified the microcapsules’ payload, performed the in vitro release experiments, and then observed correlating cell response over the following week of culturing. These demonstrations have provided guidance towards a more integrated system, which will validate the impact of the localized actuators in stimulating enhancing wound healing rates. More broadly, the eventual integrated system, incorporating both sensors and the adaptive algorithm, will be able to sense and respond to physiological changes within a wound in real-time. This work explores how wireless, deep-tissue devices coupled with external control modalities will facilitate interventions with high spatiotemporal accuracy; when combined with sensing and regulating algorithms, it will empower real-time monitoring and interventions in physiological processes. Aim 1 focused on the fabrication of such implantable microcapsule devices and Aim 2 demonstrated a method for triggering the devices using an external control modality. In Aim 3, we investigated a use case for these microcapsules to promote rapid wound healing, alongside flexible electronics, sensors, and additional actuators. To provide additional context on implantable microdevices and biocompatibility, we provide a framework for designing medical microrobotics in Appendix I and an application of a thermally-responsive hydrogel coating in Appendix II. Overall, the sum of this work illustrates the potential impact of soft microdevices for localized and on-demand applications, towards a future of spatiotemporally-targeted biological interventions.

Indiana University-Purdue University Indianapolis (IUPUI) / It is increasingly recognized that mechanical properties of substrates play a pivotal role in the regulation of cellular fate and function. However, the underlying mechanisms of cellular mechanosensing still remain a topic of open debate. Traditionally, advancements in this field have been made using polymeric substrates of adjustable stiffness with immobilized linkers. While such substrates are well suited to examine cell adhesion and migration in an extracellular matrix environment, they are limited in their ability to replicate the rich dynamics found at cell-cell interfaces. To address this challenge, we recently introduced a linker-functionalized polymer-tethered multi-bilayer stack, in which substrate stiffness can be altered by the degree of bilayer stacking, thus allowing the analysis of cellular mechanosensitivity. Here, we apply this novel biomembrane-mimicking cell substrate design to explore the mechanosensitivity of C2C12 myoblasts in the presence of cell-cell-mimicking N-cadherin linkers. Experiments are presented, which demonstrate a relationship between the degree of bilayer stacking and mechanoresponse of plated cells, such as morphology, cytoskeletal organization, cellular traction forces, and migration speed. Furthermore, we illustrate the dynamic assembly of bilayer-bound N-cadherin linkers underneath cellular adherens junctions. In addition, properties of individual and clustered N-cadherins are examined in the polymer-tethered bilayer system in the absence of plated cells. Alternatively, substrate stiffness can be adjusted by the concentration of lipopolymers in a single polymer-tethered lipid bilayer. On the basis of this alternative cell substrate concept, we also discuss recent results on a linker-functionalized single polymer-tethered bilayer substrate with a lateral gradient in lipopolymer concentration (substrate viscoelasticity). Specifically, we show that the lipopolymer gradient has a notable impact on spreading, cytoskeletal organization, and motility of 3T3 fibroblasts. Two cases are discussed: 1. polymer-tethered bilayers with a sharp boundary between low and high lipopolymer concentration regions and 2. polymer-tethered bilayers with a gradual gradient in lipopolymer concentration.