Stimuli-responsive drug delivery materials release their payloads in response to physiological or external cues and are widely reported for stimuli such as pH, temperature, ionic strength, electrical potential, or applied magnetic field. While a handful of reports exist on materials responsive to mechanical stimuli, this area receives considerably less attention. This dissertation therefore explores three-dimensional networks and polymer-metal composites as mechanoresponsive biomaterials by using mechanical force to either trigger the release of entrapped agents or change the conformation of implants. At the nanoscale, shear is demonstrated as a mechanical stimulus for the release of a monoclonal antibody from nanofibrous, low molecular weight hydrogels formed from bio-inspired small molecule gelators. Using their self-healing, shear-thinning properties, mechanoresponsive neutralization of tumor necrosis factor alpha (TNFα) in a cell culture bioassay is achieved, suggesting utility for treating rheumatoid arthritis. Reaching the microscale, mechanical considerations are incorporated within the design of cisplatin-loaded meshes for sustained local drug delivery, which are fabricated through electrospinning a blend of polycaprolactone and poly(caprolactone-co-glycerol monostearate). These meshes are compliant, amenable to stapling/suturing, and they exhibit bulk superhydrophobicity (i.e., extraordinary resistance to wetting), which sustains release of cisplatin >90 days in vitro and significantly delays tumor recurrence in an in vivo murine lung cancer resection model. This polymer chemistry/processing strategy is then generalized by applying it to the poly(lactide-co-glycolide) family of biomedical polymers. As a macroscopic approach, a tunable, tension-responsive multilayered drug delivery device is developed, which consists of a water-absorbent core flanked by two superhydrophobic microparticle coatings. Applied strain initiates coating fracture to cause core hydration and subsequent drug release, with rates dependent on strain magnitude. Finally, macroscopic, shape-changing polymer-composite materials are developed to improve the current functionality of breast biopsy markers. This shape change provides a means to prevent marker migration from its intended site—a current clinical problem. In summary, mechanoresponsive systems are described, ranging from the nano- to macroscopic scale, for applications in drug delivery and biomedical devices. These studies add to the nascent field of mechanoresponsive biomedical materials and the arsenal of drug delivery techniques required to combat cancer and other medical ailments. / 2017-10-27T00:00:00Z

Because of the latest developments in nanotechnology and the need to have new functions, a high demand for innovative materials is created. The technological requirements for new applications cannot be fulfilled by most of the well-developed materials like metals, plastics, or ceramics. Therefore, composite materials that can exhibit better properties in contrast to their single counterpart represents a valuable and interesting alternative for the development of new and more performing functional materials. In the past few years, one of the most rapidly developing fields in materials chemistry is research and development of innovative hybrid materials and nanocomposites having exceptional properties. A significant reason for this is that this group of materials closes the gaps between different scientific fields and brings together the ideal properties of the different disciplines into a single system. Conventional materials like polymers or minerals can be mixed with substances of a different kind, like biological molecules and different chemical functional groups to create unique functional materials with the help of a building block method. Inorganic and organic chemistry, physical and biological sciences are integrated in the search for new recipes in a purely interdisciplinary way to generate unique materials. Compounds that are created frequently have interesting new properties for forthcoming functional materials and technological applications. Natural materials frequently function as a model for these systems and various examples of biomimetic methods can be obtained while generating these hybrid materials. The research and development of these materials is driven by the needs of future technologies. The research carried out in this thesis is entirely based on hybrid organic-inorganic materials; hence, it consists of soft organic/bioorganic section that makes it possible to generate multifunctional materials, whereas the hard inorganic section functions as a rigid and stable platform for developing nanocarriers and imaging agents. A key domain in materials chemistry is the creation of smart materials that have the ability to respond to environmental changes or be triggered on demand. These materials have led to the creation of new technologies, like electroactive materials, electrochromic materials, biohybrid materials, sensors and membranes, etc. The required functionality can be provided by the organic or inorganic components, or from both. In this dissertation, the synthesis, methodology, and creation of three unique organic-inorganic hybrid stimuli responsive systems having targeted features for specific applications are examined. The first example is represented by supramolecular microtoroids created by spontaneous self-assembly of amphiphilic molecules and a hydrophilic polymer (chitosan), in the presence of iron (III) chloride. Light irradiation is the stimulus responsible for assembly/disassembly of this new supramolecular entities. The basis of the photo-response of the microtoroids is the photoreaction of the anthracene derivatives. In order to make these materials bio applicable, the microtoroid size was controlled and narrowed down to nanometers, which has led to our second system called metal organic complexes (MOCs). In this system, chitosan was replaced by PNIPAM polymer at optimized concentrations. The reversible thermo-response of MOCs comes from the phase transition ability of PNIPAM. The third hybrid material is the core-shell system consisting of mesoporous organosilica coated with iron oxide nanoparticles, used for cargo delivery and cell imaging. The magnetic-response of the core-shell system results from the strong magnetic properties of iron oxide nanoparticles, while the presence of PMOs increased its biocompatibility. Our research on such organic-inorganic hybrid materials represents a promising development in the field of materials chemistry. Due to the possibility of mixing various properties in a single material, a variety of combinations regarding possible materials and applications have emerged.

Nanofabrication techniques produce materials with enhanced physicochemical properties through a combination of nanoscale roughness and the use of chemically diverse polymers which enable advanced applications in separation science (air/water purification), tissue engineering, and biosensing. Since the late 1990’s, electrospinning has been extensively studied and utilized to produce nano- to microfiber meshes with 3D porosity on the gram scale. By combining a high surface area to volume ratio and tunable surface chemistry, electrospinning is a facile platform for generating non-woven polymeric fibers for many biomedical and industrial applications. This thesis describes three applications of electrospun nano- and microfiber meshes spun from both commercially available and novel polymer systems for: 1) oil and water separation after an accidental oil spill; 2) ultraviolet light controlled protein and cell patterning throughout 3-dimensional nanofiber meshes; and 3) novel diagnostic platform by combining electrospun nanofiber meshes with solid state nanopores for enhanced single molecule nucleic acid and protein detection. Each application embodies the philosophy that electrospun materials have the potential to solve a wide variety of problems by simply tuning the physicochemical properties and mesh morphologies towards the design requirements for a specific problem. For example, to solve the problem of recovering crude oil after an oil spill while generating a minimal waste burden, a hydrophobic and biodegradable microfiber mesh was designed to repeatedly separate oil and water and naturally biodegrade after use. In order to solve the problem of spatiotemporal placement of cells within a 3-dimensional tissue engineering construct, an ultraviolet light activated mesh was designed to transition from hydrophobic (water impermeable) to hydrophilic (water permeable) upon exposure to ultraviolet light facilitating protein and cell patterning. Finally to address two problems with single molecule solid state nanopore biosensors, namely rapid nucleic acid translocation rates and limited protein identification capabilities, a new biosensor platform was developed based on two novel polymeric systems which were synthesized and electrospun into high surface area nanofiber mesh coatings. / 2018-02-17T00:00:00Z

No description available.

Waveguide architectures were inscribed within two different stimuli-responsive hydrogels capable of actuation. An electroactive hydrogel, which deforms when placed within an electric field, is demonstrated as a method for remote actuation and steering of light outputs. Lattices of waveguide with diameters on the microscale were embedded within hydrogel prisms, achieved through a nonlinear light propagation process known as self-trapping. This process is a result of balance between the natural divergence of light and self-focusing effects caused by an irreversible positive refractive index change during photopolymerization. Waveguiding structures are inscribed in the material because of this process. Square (2D) and near-cubic (3D) lattices were inscribed in hydrogel prisms, demonstrating the ability to remotely steer one or two light outputs simultaneously using an electric field. The overall optical effect is reminiscent of camouflaging techniques observed in marine creatures (ie. cephalopods). Additionally, a novel volumetric 3D printing technique previously demonstrated by the Saravanamuttu group was implemented to fabricate hydrogel cylinders capable of photothermal actuation. Coupling a thermoresponsive hydrogel material with a photoabsorber, areas irradiated by a light source are observed to contract. These contractions lead to the deflection of waveguiding cylinders towards the light source, reminiscent of the phototropic behaviours observed in particular plants (ie. sunflowers). The results of these studies provide insight for the fabrication of functional materials through nonlinear light propagation. Understanding these systems could provide knowledge for the fabrication of other stimuli-responsive materials with light-guiding properties. / Thesis / Master of Science (MSc)

Developing a drug delivery vehicle that can control the release kinetics of a therapeutic drug on demand has great potential to improve health by allowing health care professionals to maintain the drug concentration in its therapeutic window and increase the efficiency at which treatment is administered. On-demand release can be triggered by a range of stimuli including magnetic, radiation, and ultrasound activation. Of the three, ultrasound is the only one indiscriminate of the chemical properties of the material and is the most widely available clinically, which makes it versatile and applicable for many systems. However, existing strategies that use ultrasound as a release stimulus either pop the microcapsules altogether (enabling no subsequent effective control over the kinetics of drug release) or require continuous ultrasonic administration (typically impractical in a clinical setting), both of which are suboptimal. Overcoming at least of these shortcomings would vastly improve on the technology. In this thesis, microcapsules with a complex shell were fabricated using a modified electrohydrodynamic approach named immersion coaxial electrospraying, which allowed for an increased polymer loading in the shell and improved manipulation of microcapsule size. The complex shell structure of the microcapsules incorporated silica microparticles that acted as corks plugging pores between the inside and outside of the microcapsule. The modified microcapsules were shown to release their payload in the presence of a focused ultrasound signal, while uncorked microcapsules do not release. Release kinetics were shown to be adjustable based on the number of corks initially present in the shell of the microcapsule material. Altogether, the cork-shell microcapsules fabricated in this thesis show promise as a tunable on-demand drug delivery vehicle that is able to better control release compared to conventional ultrasound triggered microcapsules. / Thesis / Master of Applied Science (MASc) / This thesis focuses on the fabrication of complex microcapsules that can be deliver therapeutic drugs on-demand using ultrasound waves. These microcapsules are composed of a water-based core and a biologically inert shell into which particles are embedded. Upon the application of ultrasound, these embedded particles (like corks on a bottle) are popped out to release the “corks” from the shell, creating pores from which the drug in the microcapsule core can be released. In the absence of ultrasound signals, the microcapsules do not release any of their contents, making these effective for “on-demand” release. These microcapsules are made using a modified process based on electrospraying which allows very precise control over the microcapsules’ physical properties, incorporating a key modification that overcomes an inherent issue with the general technique. These microcapsules also improve on currently used ultrasound triggered drug delivery systems by requiring shorter periods of ultrasound and/or enabling better control over the dynamics of drug release following the ultrasound pulse.

The development of controllable drug delivery systems is crucial for reducing toxicity and minimizing off-target drug effects for patients undergoing chemotherapy. Metal–organic frameworks (MOFs) are a class of hybrid materials that have become of interest in the field of drug delivery. MOFs are composed of metal nodes and organic bridging ligands. MOFs have a wide range of desirable properties including chemical stability, high porosity, and structural tunability which have positioned them as successful drug carriers. Through judicious choice of linker, stimuli-responsive MOFs can be synthesized to achieve precise control over cargo release. Previously, our lab developed a novel light-responsive drug delivery system using a framework known as UiO-AZB (UiO= University of Oslo, AZB=4,4ʹ-azobenzenedicarboxylic acid). This MOF contains a photoswitchable azobenzene linker. Upon irradiation with ultraviolet light, the compound undergoes a structural change known as photoisomerization, resulting in degradation of the MOF structure and simultaneous release of encapsulated cargo. To improve the clinical relevance of our framework, we focus on developing synthetic methods for production of visible light-responsive azobenzene photoswitches. A green light-responsive MOF (UiO-AZB-F) containing a 4,4ʹ-(diazene-1,2- diyl)bis(3,5-difluorobenzoic acid) linker was developed as a drug delivery system for the treatment of colorectal cancer. Our work also focuses on optimizing various aspects of MOF design to maximize and diversify cargo loading and precisely control cargo release rates. A combined computational and experimental investigation of drug adsorption process reveals that the presence of solvent can significantly impact the adsorption of drug molecules within MOF pores. To address these concerns, a variety of drug loading procedures were screened to determine conditions for maximizing the loading of diverse drug cargoes. Conditions for the loading of single agents as well as chemotherapy cocktails were explored to expand the application of our delivery platform to other cancer types including lung, pancreatic, bladder and cervical. To modulate the release of cargo, a series of MOFs containing precise ratios of green light-responsive linker were synthesized to create a platform for sustained release. Remarkably, several MOF derivatives showed enhancement in drug adsorption, highlighting the important role of host–guest interactions in nanocarrier development. Holistically, this work highlights the promise of stimuli-responsive MOFs as drug delivery platforms. / Doctor of Philosophy / Cancer is one of the leading causes of death worldwide. In 2021, nearly 2 million people in the U.S. were diagnosed with cancer. For patients undergoing chemotherapy treatment, the side effects of potent chemotherapeutics are often debilitating. Drug- delivery systems serve as a promising platform for localizing the delivery of chemotherapeutic drugs within a diseased area. When chemotherapeutics are delivered precisely to tumor regions via drug delivery systems, systemic side effects are significantly diminished. In this work, a series of materials known as metal–organic frameworks (MOFs) are developed as carriers for chemotherapeutic cargo. Due to the incorporation of photoactivated compounds within the backbone, these MOFs can be degraded on-demand through green light irradiation. As the framework degrades into small molecule components, drug cargo is simultaneously released. Methods for maximizing MOF drug loadings, diversifying the types of cargo that can be incorporated, and modifying cargo release rates are also investigated. This work establishes stimuli-responsive MOFs as promising materials for on-demand drug delivery.

Nanoparticle-based delivery vehicles have received substantial interest in the field of drug delivery particularly pertaining to chemotherapeutics. By virtue of their size, nanoscale drug delivery vehicles overcome many obstacles encountered by traditional systems. Moreover, nanocarriers can be fabricated to be ‘smart’, meaning they can be responsive to internal stimuli relating to the microenvironment of the tumor and/or external stimuli that can be delivered non-invasively from outside of the body. One such external trigger is ultrasound, well-known for its role in biomedical imaging based on its wide availability, non-invasiveness, and safety but increasingly being applied for drug delivery. This thesis proposes solutions to two key challenges associated with locally-targeted polymer-based drug delivery: enhanced tumor accumulation and externally-triggered control over release kinetics. In the former case, brush polymer PLA-PEG analogues are synthesized and explored to correlate how the architecture of these brush blocks affects the resulting self-assembled nanoparticle size, zeta potential, cytotoxicity in vitro, circulation time, and accumulation profiles in vivo. Indeed, brush copolymer analogues allow for copolymerization with additional monomers while conserving ‘stealth properties of linear copolymers, as well as exhibit superior circulation times and longer-term tumor accumulation. In the latter case, a new ultrasound-triggered drug delivery platform is designed consisting of a hollow polymeric shell in which silica “corks” are entrapped; the application of ultrasound can exploit the high difference in the compressibility between the polymeric shell and the silica corks to pop out or otherwise perturb the cork particles, allowing for both on-demand drug release as well as a pulsatile release profiles to be achieved. Overall, by manipulating the surface properties and/or morphologies of polymer-based micro/nanoparticles, the results of this thesis show that key challenges in local drug delivery can be addressed and applied specifically to applications in cancer therapy. / Dissertation / Doctor of Philosophy (PhD) / Drug delivery vehicles attempt to address many of the shortcomings of traditional therapeutics, in particular their low solubility and a lack of tissue targeting, which result in poor efficacy and unwanted side-effects. Polymers specifically have been commonly employed in biomedical applications as there are a wide range of biodegradable polymers that do not cause adverse effects during intended application and can be removed from the body through normal biological function. More recently, more advanced, ‘smart’ materials have been developed that can respond to internal or external stimuli to better address treatment needs. This thesis presents novel polymer-based drug delivery vehicles with new structures useful to passively target particular sites in the body and/or alter drug release profiles, enabling improved drug efficacy and reduced side-effects.

Yes / This study shows how highly branched poly(N-isopropyl acrylamide) (HB-PNIPAM) with a chain pendant solvatochromic dye (Nile red) could provide a fluorescence signal, as end groups bind to bacteria and chain segments become desolvated, indicating the presence of bacteria. Vancomycin was attached to chain ends of HB-PNIPAM or as pendant groups on linear polymers each containing Nile red. Location of the dye was varied between placement in the core of the branched polymer coil or the outer domains. Both calorimetric and fluorescence data showed that branched polymers responded to binding of both the peptide target (D-Ala-D-Aa) and bacteria in a different manner than analogous linear polymers; binding and response was more extensive in the branched variant. The fluorescence data showed that only segments located in the outer domains of branched polymers responded to binding of Gram-positive bacteria with little response when linear analogous polymer or branched polymer with the dye in the inner core was exposed to Staphylococcus aureus. / Innovate UK/Smith and Nephew Ltd. (UK) (TSB 103988) and by MRC (MR/N501888/2).

Das corneale Endothel bildet die innere, einschichtige Zelllage der Cornea und ist für die Aufrechterhaltung der cornealen Transparenz zuständig. Krankheiten oder Verletzungen des cornealen Endothels können zu schweren Beeinträchtigungen des Sehvermögens führen und eine corneale Transplantation erforderlich machen. Der während und nach der Operation auftretende endotheliale Zellverlust erschwert das Überleben des Transplantates. Darum besteht ein Hauptziel des cornealen Tissue Engineerings in der Bereitstellung von transplantierbaren humanen cornealen Endothelzellsheets (HCEC-Sheets) mit einer adäquaten Zelldichte. Thermo-responsive Zellkulturträger fanden für die schonende, enzymfreie Gewinnung von Zellsheets für verschiedene Gewebetypen bereits Verwendung. HCEC stellen in diesem Kontext einen besonderen Fall dar, da sie eine starke Adhäsion zu ihrem Kultursubstrat ausbilden, was deren schonende, thermisch induzierte Ablösung als funktionelles Zellsheet erschwert. Im Rahmen dieser Arbeit wurde ein neuartiger thermo-responsiver Zellkulturträger entwickelt. Dieser basiert auf dem durch Elektronenbestrahlung immobilisierten und vernetzten thermo-responsiven Polymer Poly(vinylmethylether) (PVME) sowie dem alternierenden Co-Polymer Poly(vinylmethylehter-alt-maleinsäureanhydrid) (PVMEMA) als biofunktionalisierbare Komponente. Die Kombination dieser Polymere führte zur Etablierung eines thermo-responsiven Zellkulturträgers, dessen physikochemische und biomolekulare Eigenschaften in weiten Grenzen einstellbar und dadurch an die spezifischen Anforderungen von HCEC anpassbar waren. Das PVME-PVMEMA-Blend ermöglichte die Bildung konfluenter HCEC-Monolayer mit den morphologischen Grundlagen für ein funktionelles corneales Endothelgewebe. Durch Inkorporation von Poly(N-isopropylacrylamid) (PNiPAAm) als weitere thermo-responsive Polymerkomponente konnte das Ablösungsverhalten funktioneller HCEC-Sheets weiter verbessert werden. In einem weiteren Schritt erfolgte der Transfer abgelöster HCEC-Sheets auf ein planares, biofunktionalisiertes Kultursubstrat sowie auf endothelfreie porcine Corneae. Die HCEC-Sheets wurden auch nach dem Transfer umfassend biologisch analysiert. Diese Arbeit legt einen Grundstein für die Bereitstellung klinisch anwendbarer Alternativen für das Tissue Engineering von cornealem Gewebe.