Laminated chemical and physical micro-jet actuators based on conductive media

This dissertation presents the development of electrically-powered, lamination-based microactuators for the realization of large arrays of high impulse and short duration micro-jets with potential applications in the field of micro-electro-mechanical systems (MEMS). Microactuators offer unique control opportunities by converting the input electrical or chemical energy stored in a propellant into useful mechanical energy. This small and precise control obtained can potentially be applied towards aerodynamic control and transdermal drug delivery applications. This thesis discusses the development of both chemical and physical microactuators and characterizes their performance with focus towards the feasibility of using them for a specific application. The development of electrically powered microactuators starts by fabricating an array of radially firing microactuators using lamination-based micro fabrication techniques that potentially enable batch fabrication at low cost. The microactuators developed in this thesis consist of three main parts: a micro chamber in which the propellant is stored; two electrode structures through which electrical energy is supplied to the propellant; and a micro nozzle through which the propellant or released gases from the propellant are expanded as a jet. The fabricated actuators are then integrated with MEMS-process-compatible propellants and optimized to produce rapid ignition of the propellant and generate a fluidic jet. This rapid ignition is achieved either by making the propellant itself conductive, thus, passing an electric current directly through the propellant; or by discharging an arc across the propellant by placing it between two closely spaced electrodes. The first concept is demonstrated with chemical microactuators for the application of projectile maneuvering and the second concept is demonstrated with physical microactuators for transdermal drug delivery application. For both the actuators, the propellant integrated microactuators are characterized for performance in terms of impulse delivered, thrust generated and duration of the jet. The experimentally achieved results are validated by comparing with results from theoretical modeling. Finally, the feasibility of using chemical microactuators for maneuvering the path of a 25 mm projectile spinning at 500 Hz is discussed and the feasibility of applying the physical microactuators for increasing skin's permeability to drug analog molecules is studied.Ph.D.Committee Chair: Allen, Mark; Committee Member: Allen, Sue; Committee Member: Glezer, Ari; Committee Member: Koros, Williams; Committee Member: Prausnitz, Mar

Improved inhalation therapies of brittle powders

textAdvancements in pulmonary drug delivery technologies have improved the use of dry powder inhalation therapy to treat respiratory and systemic diseases. Despite remarkable improvements in the development of dry powder inhaler devices (DPIs) and formulations in the last few years, an optimized DPI system has yet to be developed. In this work, we hypothesize that Thin Film Freezing (TFF) is a suitable technology to improve inhalation therapies to treat lung and systemic malignancies due to its ability to produce brittle powder with optimal aerodynamic properties. Also, we developed a performance verification test (PVT) for the Next Generation Cascade Impactor (NGI), which is one of the most important in vitro characterization methods to test inhalation. In the first study, we used TFF technology to produce amorphous and brittle particles of rapamycin, and compared the in vivo behavior by the pharmacokinetic profiles, to its crystalline counterpart when delivered to the lungs of rats via inhalation. It was found that TFF rapamycin presented higher in vivo systemic bioavailability than the crystalline formulation. Subsequently, we investigated the use of TFF technology to produce triple fixed dose therapy using formoterol fumarate, tiotropium bromide and budesonide as therapeutic drugs. We investigated applications of this technology to powder properties and in vitro aerosol performance with respect to single and combination therapy. As a result, the brittle TFF powders presented superior properties than the physical mixture of micronized crystalline powders, such as excellent particle distribution homogeneity after in vitro aerosolization. Lastly, we developed a PVT for the NGI that may be applicable to other cascade impactors, by investigating the use of a standardized pressurized metered dose inhaler (pMDI) with the NGI. Two standardized formulations were developed. Formulations were analyzed for repeatability and robustness, and found not to demonstrate significant differences in plate deposition using a single NGI apparatus. Variable conditions were introduced to the NGI to mimic operator and equipment failure. Introduction of the variable conditions to the NGI was found to significantly adjust the deposition patterns of the standardized formulations, suggesting that their use as a PVT could be useful and that further investigation is warranted.Pharmaceutical Science

Accelerating development of suspension pressurized metered dose inhaler formulations: innovative techniques to evaluate particle stability

This thesis presents several innovative techniques to rapidly evaluate particle stability in suspension-based pressurized metered dose inhalers (pMDIs). Chapter 1 reviews techniques available to evaluate particle stability in pMDIs, discussing categories such as particle properties, suspension quality, polymorphism, and long term stability. Emerging techniques such as Liquid Colloidal Probe Microscopy (CPM), Nano X-ray Computer Tomography (NanoXCT), and Pressurized Isothermal Microcalorimetry possess the potential for accelerating pMDI formulation and are developed through the work embodied within this thesis. Chapters 2, 3, and 4 discuss the improvement and application of liquid CPM to evaluate nano-scale interactions between particles of various porosities in a model propellant. Particle porosity/morphology was found to have a significant effect on these interactions; however, direct measurement of internal particle architecture can be challenging. Thus, in chapter 5, a novel technique using NanoXCT was developed to visualize and quantify the internal porosity of inhalable sized particles with a resolution of 50 nm. It is necessary to control morphology through various manufacturing processes such as freeze and spray drying, since these processes can affect particle physical stability in propellant; thus, in chapter 6 an innovative technique using isothermal microcalorimetry was developed to directly evaluate particle stability in actual pMDI formulations. The versatility of the technique is further demonstrated in Chapter 7, through the evaluation of various other pMDI particle parameters such as amorphicity, excipient compatibility, and moisture ingress

Accelerating development of suspension pressurized metered dose inhaler formulations: innovative techniques to evaluate particle stability

This thesis presents several innovative techniques to rapidly evaluate particle stability in suspension-based pressurized metered dose inhalers (pMDIs). Chapter 1 reviews techniques available to evaluate particle stability in pMDIs, discussing categories such as particle properties, suspension quality, polymorphism, and long term stability. Emerging techniques such as Liquid Colloidal Probe Microscopy (CPM), Nano X-ray Computer Tomography (NanoXCT), and Pressurized Isothermal Microcalorimetry possess the potential for accelerating pMDI formulation and are developed through the work embodied within this thesis. Chapters 2, 3, and 4 discuss the improvement and application of liquid CPM to evaluate nano-scale interactions between particles of various porosities in a model propellant. Particle porosity/morphology was found to have a significant effect on these interactions; however, direct measurement of internal particle architecture can be challenging. Thus, in chapter 5, a novel technique using NanoXCT was developed to visualize and quantify the internal porosity of inhalable sized particles with a resolution of 50 nm. It is necessary to control morphology through various manufacturing processes such as freeze and spray drying, since these processes can affect particle physical stability in propellant; thus, in chapter 6 an innovative technique using isothermal microcalorimetry was developed to directly evaluate particle stability in actual pMDI formulations. The versatility of the technique is further demonstrated in Chapter 7, through the evaluation of various other pMDI particle parameters such as amorphicity, excipient compatibility, and moisture ingress

A new era of pulmonary delivery of nano-antimicrobial therapeutics to treat chronic pulmonary infections

Pulmonary infections may be fatal especially in immunocompromised patients and patients with underlying pulmonary dysfunction, such as those with cystic fibrosis, chronic obstructive pulmonary disorder, etc. According to the WHO, lower respiratory tract infections ranked first amongst the leading causes of death in 2012, and tuberculosis was included in the top 10 causes of death in low income countries, placing a considerable strain on their economies and healthcare systems. Eradication of lower respiratory infections is arduous, leading to high healthcare costs and requiring higher doses of antibiotics to reach optimal concentrations at the site of pulmonary infection for protracted period. Hence direct inhalation to the respiratory epithelium has been investigated extensively in the past decade, and seems to be an attractive approach to eradicate and hence overcome this widespread problem. Moreover, engineering inhalation formulations wherein the antibiotics are encapsulated within nanoscale carriers could serve to overcome many of the limitations faced by conventional antibiotics, like difficulty in treating intracellular pathogens such as mycobacteria spp. and salmonella spp., biofilm-associated pathogens like Pseudomonas aeruginosa and Staphylococcus aureus, passage through the sputum associated with disorders like cystic fibrosis and chronic obstructive pulmonary disorder, systemic side effects following oral/parenteral delivery and inadequate concentrations of antibiotic at the site of infection leading to resistance. Encapsulation of antibiotics in nanocarriers may help in providing a protective environment to combat antibiotic degradation, confer controlled-release properties, hence reducing dosing frequency, and may increase uptake via specific and non-specific targeting modalities. Hence nanotechnology combined with direct administration to the airways using commercially available delivery devices, is a highly attractive formulation strategy to eradicate microorganisms from the lower respiratory tract, which might otherwise present opportunities for multi-drug resistance

A New Era of Pulmonary Delivery of Nano-antimicrobial Therapeutics to Treat Chronic Pulmonary Infections

Pulmonary infections may be fatal especially in immunocompromised patients and patients with underlying pulmonary dysfunction, such as those with cystic fibrosis, chronic obstructive pulmonary disorder, etc. According to the WHO, lower respiratory tract infections ranked first amongst the leading causes of death in 2012, and tuberculosis was included in the top 10 causes of death in low income countries, placing a considerable strain on their economies and healthcare systems. Eradication of lower respiratory infections is arduous, leading to high healthcare costs and requiring higher doses of antibiotics to reach optimal concentrations at the site of pulmonary infection for protracted periods. Hence direct inhalation to the respiratory epithelium has been investigated extensively in the past decade, and seems to be an attractive approach to eradicate and hence overcome this widespread problem. Moreover, engineering inhalation formulations wherein the antibiotics are encapsulated within nanoscale carriers could serve to overcome many of the limitations faced by conventional antibiotics, like difficulty in treating intracellular pathogens such as mycobacteria spp. and salmonella spp., biofilmassociated pathogens like Pseudomonas aeruginosa and Staphylococcus aureus, passage through the sputum associated with disorders like cystic fibrosis and chronic obstructive pulmonary disorder, systemic side effects following oral/parenteral delivery and inadequate concentrations of antibiotic at the site of infection leading to resistance. Encapsulation of antibiotics in nanocarriers may help in providing a protective environment to combat antibiotic degradation, confer controlled-release properties, hence reducing dosing frequency, and may increase uptake via specific and non-specific targeting modalities. Hence nanotechnology combined with direct administration to the airways using commercially available delivery devices, is a highly attractive formulation strategy to eradicate microorganisms from the lower respiratory tract, which might otherwise present opportunities for multi-drug resistance

Biomedical metal–organic framework materials : perspectives and challenges

The authors gratefully acknowledge financial support from the German Research Foundation (DFG: LA2937/4-1; SH1223/1-1; SFB 1066; GRK/RTG 2735 (project number 331065168)), the German Federal Ministry of Research and Education (BMBF: Gezielter Wirkstofftransport, PP-TNBC, Project No. 16GW0319K) and the European Research Council (ERC: Meta-Targeting (864121)). The financial support from Welch Foundation (AT-1989-20220331) and from the Human Frontier Science Program (HFSP, within the project RGP0047/2022) are also acknowledged. The authors thank the European Union (European Cooperation in Science and Technology) for the COST Action EU4MOFs (CA22147). Figures were created using BioRender.com.Metal–organic framework (MOF) materials are gaining significant interest in biomedical research, owing to their high porosity, crystallinity, and structural and compositional diversity. Their versatile hybrid organic/inorganic chemistry endows MOFs with the capacity to retain organic (drug) molecules, metals, and gases, to effectively channel electrons and photons, to survive harsh physiological conditions such as low pH, and even to protect sensitive biomolecules. Extensive preclinical research has been carried out with MOFs to treat several pathologies and, recently, their integration with other biomedical materials such as stents and implants has demonstrated promising performance in regenerative medicine. However, there remains a significant gap between MOF preclinical research and translation into clinically and societally relevant medicinal products. Here, the intrinsic features of MOFs are outlined and their suitability to specific biomedical applications such as detoxification, drug and gas delivery, or as (combination) therapy platforms is discussed. Furthermore, relevant examples of how MOFs have been engineered and evaluated in different medical indications, including cancer, microbial, and inflammatory diseases is described. Finally, the challenges facing their translation into the clinic are critically examined, with the goal of establishing promising research directions and more realistic approaches that can bridge the translational gap of MOFs and MOF‐containing (nano)materials.Publisher PDFPeer reviewe