Solutes are often most efficiently deployed in discrete pulses, for example in the delivery of herbicides or drugs. Manual application of each pulse can be labor-intensive, automated application of each pulse can be capital intensive, and both are often costly and impractical. Barrier-Mediated Pulsatile Release (BMPR) systems offer a materials-based alternative for automated pulsatile drug delivery, without pumps, power supplies, or complex circuitry. While earlier materials-based approaches such as delayed-release microcapsules are limited to two or three pulses due to the independent nature of each pulse’s timing control, BMPR systems link the timing of each pulse to the previous pulse. Each dose of drug is sequestered in its own stimuli-sensitive depot, releasing only upon contact with the stimulant. These depots are stacked with sacrificial barriers in between, each of which block the stimulant for a predetermined time. For instance, layers of soluble drug may be separated by degradable polymer layers. Water, as the stimulant, will erode the polymer layer over a fixed period of time, followed by quick dissolution and release of the underlying drug and the start of degradation for the next polymer layer. This example, however, is quickly limited by irregular polymer erosion, a single stimulant (water), and difficulty in scaling delay times. The research work presented in this thesis reports the development of a generalized BMPR system which overcomes those limitations. Model drugs (methylene blue and methyl orange) were immobilized in a pH-sensitive polymer [poly(methyl methacrylate-co-dimethylaminoethyl methacrylate)] which released only at low pH. Zinc oxide (ZnO) nanoparticles immobilized in a pH-insensitive matrix [poly(vinyl alcohol)] served as the barrier layer. The time required for acid to penetrate the barrier layer scaled with the ZnO concentration and with the square of the polymer thickness, allowing wide scaling of the delay time with only minor changes to the barrier layer. Harnessing the swelling pressure of the acid-sensitive hydrogel, each barrier/depot bilayer can delaminate upon solute release, directly exposing the next bilayer to the stimulant source. This system has demonstrated tuned release using a citric acid stimulant to produce up to ten pulses of model drug (methylene blue) over various preset timescales. This system has also demonstrated the alternate release of multiple solutes (methylene blue and methyl orange) at regular time intervals up to five pulses from a single BMPR device. For non-delaminating BMPR systems, spent bilayers impede stimulant diffusion to the inner layers and solute diffusion from the inner layers, increasing the delay time and the pulse width. To predict these changes, a computational model was constructed in FORTRAN. This model was extensively explored over a wide range of parameter space to understand the release behavior of various kinds of non-delaminating BMPR systems. The computer model also validates the performances of experimental delaminating BMPR system. This model can be used to guide the physical modeling of BMPR systems. The model also allows to incorporate variety of stimulants other than just acid. BMPR technology introduces efforts to further generalize the delivery strategy by incorporating glucose as a stimulant.

<p>Injectable, in-situ gelling magnetic plum pudding hydrogel composites were fabricated by entrapping superparamagnetic iron oxide nanoparticles (SPIONs) and thermosensitive N-isopropylacrylamide (NIPAM)-co–N-isopropylmethacrylamide (NIPMAM) microgels in a pNIPAM-hydrazide/carbohydrate-aldehyde hydrogel matrix. The resulting composites exhibited significant, repeatable pulsatile release of 4 kDa FITC-dextran upon exposure to an alternating magnetic field. The pulsatile release from the composites could be controlled by altering the volume phase transition temperatures of the microgel particles (with VPTTs over 37°C corresponding to improved pulsatile release) and changing the microgel content of the composite (with higher microgel content corresponding to higher pulsatile release). By changing the ratio of dextran-aldehyde (which deswells at physiological temperature) to CMC-aldehyde (which swells at physiological temperature) in the composites, bulk hydrogel swelling and thus pulsatile release could be controlled; specifically, lower CMC-aldehyde contents resulted in little to no composite swelling, improving pulsatile release. <em>In vitro</em> cytotoxicity testing demonstrated that the composite precursors exhibit little to no cytotoxicity up to a concentration of 2000 µg/mL. Together, these results suggest that this injectable hydrogel-microgel composite hydrogel may be a viable vehicle for <em>in vivo</em>, pulsatile drug delivery.<strong></strong></p> / Master of Applied Science (MASc)