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- Creators: Arizona State University
- Creators: Harrington Bioengineering Program
Description
Controlled release formulations for local, in vivo drug delivery are of growing interest to device manufacturers, research scientists, and clinicians; however, most research characterizing controlled release formulations occurs in vitro because the spatial and temporal distribution of drug delivery is difficult to measure in vivo. In this work, in vivo magnetic resonance imaging (MRI) of local drug delivery is performed to visualize and quantify the time resolved distribution of MRI contrast agents. I find it is possible to visualize contrast agent distributions in near real time from local delivery vehicles using MRI. Three dimensional T1 maps are processed to produce in vivo concentration maps of contrast agent for individual animal models. The method for obtaining concentration maps is analyzed to estimate errors introduced at various steps in the process. The method is used to evaluate different controlled release vehicles, vehicle placement, and type of surgical wound in rabbits as a model for antimicrobial delivery to orthopaedic infection sites. I are able to see differences between all these factors; however, all images show that contrast agent remains fairly local to the wound site and do not distribute to tissues far from the implant in therapeutic concentrations. I also produce a mathematical model that investigates important mechanisms in the transport of antimicrobials in a wound environment. It is determined from both the images and the mathematical model that antimicrobial distribution in an orthopaedic wounds is dependent on both diffusive and convective mechanisms. Furthermore, I began development of MRI visible therapeutic agents to examine active drug distributions. I hypothesize that this work can be developed into a non-invasive, patient specific, clinical tool to evaluate the success of interventional procedures using local drug delivery vehicles.
ContributorsGiers, Morgan (Author) / Caplan, Michael R (Thesis advisor) / Massia, Stephen P (Committee member) / Frakes, David (Committee member) / McLaren, Alex C. (Committee member) / Vernon, Brent L (Committee member) / Arizona State University (Publisher)
Created2013
Description
Many therapeutics administered for some of the most devastating illnesses can be toxic and result in unwanted side effects. Recent developments have been made in an alternative treatment method, called gene therapy. Gene therapy has potential to rectify the genetic defects that cause a broad range of diseases. Many diseases, such as cancer, cystic fibrosis, and acquired immunodeficiency (AIDS) already have gene therapy protocols that are currently in clinical trials. Finding a non-toxic and efficient gene transfer method has been a challenge. Viral vectors are effective at transgene delivery however potential for insertion mutagenesis and activation of immune responses raises concern. For this reason, non-viral vectors have been investigated as a safer alternative to viral-mediated gene delivery. Non-viral vectors are also easy to prepare and scalable, but are limited by low transgene delivery efficacies and high cytotoxicity at effective therapeutic dosages. Thus, there is a need for a non-toxic non-viral vector with high transgene efficacies. In addition to the hurdles in finding a material for gene delivery, large-scale production of pharmaceutical grade DNA for gene therapy is needed. Current methods can be labor intensive, time consuming, and use toxic chemicals. For this reason, an efficient and safe method to collect DNA is needed. One material that is currently being explored is the hydrogel. Hydrogels are a useful subclass of biomaterials, with a wide variety of applications. This class of biomaterials can carry up to a thousand times their weight in water, and are biocompatible. At smaller dimensions, referred to as micro- and nanogels, they are very useful for many biomedical applications because of their size and ability to swell. Based on a previously synthesized hydrogel, and due to the advantages of smaller dimension in biomedical applications, we have synthesized aminoglycoside antibiotic based nanogels and microgels. Microgels and nanogels were synthesized following a ring opening polymerization of epoxide-containing crosslinkers and polyamine-containing monomers. The nanogels were screened for their cytocompatibilities and transfection efficacies, and were compared to polyethylenimine (PEI), a current standard for polymer-mediated transgene delivery. Nanogels demonstrated minimal to no toxicity to the cell line used in the study even at high concentrations. Due to the emerging need for large-scale production of DNA, microgels were evaluated for their binding capacity to plasmid DNA. Future work with the aminoglycoside antibiotic-based nanogels and microgels developed in this study will involve optimization of nanogels and microgels to facilitate in better transgene delivery and plasmid DNA binding, respectively.
ContributorsMallik, Amrita Amy (Author) / Rege, Kaushal (Thesis advisor) / Dai, Lennore (Committee member) / Nielsen, David (Committee member) / Arizona State University (Publisher)
Created2014
Description
The central theme of this dissertation is to understand the chemical processing science of advanced ceramic materials for biomedicine, including therapy and imaging. The secondary component focuses on the chemical processing of energy materials.
Recently, layered double hydroxide (LDH) nanoparticles (NPs) with various intercalated compounds (e.g. fluorescent molecules, radio-labeled ATP, vitamins, DNA, and drugs) have exhibited versatility and promise as a combined therapeutic and diagnostic (i.e. theranostic) vector. However, its eventual acceptance in biomedicine will be contingent on understanding the processing science, reproducibly synthesizing monodispersed NPs with controlled mean particle size (MPS), and ascertaining the efficacy of the NPs for drug delivery and imaging. First, statistical design of experiments were used to optimize the wet chemistry synthesis of (Zn, Al)-LDH NPs. A synthesis model, which allows the synthesis of nearly monodispersed NPs with controlled MPS, was developed and experimentally verified. Also, the evolution of the nanostructure was characterized, from coprecipitation to hydrothermal treatment, to identify the formation mechanisms. Next, the biocompatibility, cellular uptake and drug delivery capability of LDH NPs were studied. In an in vitro study, using cultured pancreatic adenocarcinoma BXPC3 cells, valproate-intercalated LDH NPs showed an improved efficacy (~50 fold) over the sodium valproate alone. Finally, Gd(DTPA)-intercalated LDH NPs were synthesized and characterized by proton (1H) nuclear magnetic resonance. The longitudinal relaxivity (r1) of 28.38 s-1 mM-1, which is over 6 times higher than the clinically approved contrast agent, Gd(DTPA), demonstrated the potential of this vector for use in magnetic resonance imaging.
Visible light-transparent single metal-semiconductor junction devices, which convert ultraviolet photon energy into high open circuit voltage (Voc>1.5-2 V), are highly desirable for transparent photovoltaics that can potentially power an electrochromic stack for smart windows. A Schottky junction solar cell, comprised of sputtered ZnO/ZnS heterojunction with Cr/Au contacts, was fabricated and an Voc of fî1.35 V was measured. Also, a low-cost route to form ZnO/ZnS heterojunctions by partial sulfurization of solution-grown ZnO thin films (350 nm-5 fÝm thick; conductivity comparable to phosphorus-doped Si) was demonstrated. A final study was on a cathode material for Li-ion batteries. Phase-pure LiFePO4 powders were synthesized by microwave-assisted sol-gel method and characterized.
Recently, layered double hydroxide (LDH) nanoparticles (NPs) with various intercalated compounds (e.g. fluorescent molecules, radio-labeled ATP, vitamins, DNA, and drugs) have exhibited versatility and promise as a combined therapeutic and diagnostic (i.e. theranostic) vector. However, its eventual acceptance in biomedicine will be contingent on understanding the processing science, reproducibly synthesizing monodispersed NPs with controlled mean particle size (MPS), and ascertaining the efficacy of the NPs for drug delivery and imaging. First, statistical design of experiments were used to optimize the wet chemistry synthesis of (Zn, Al)-LDH NPs. A synthesis model, which allows the synthesis of nearly monodispersed NPs with controlled MPS, was developed and experimentally verified. Also, the evolution of the nanostructure was characterized, from coprecipitation to hydrothermal treatment, to identify the formation mechanisms. Next, the biocompatibility, cellular uptake and drug delivery capability of LDH NPs were studied. In an in vitro study, using cultured pancreatic adenocarcinoma BXPC3 cells, valproate-intercalated LDH NPs showed an improved efficacy (~50 fold) over the sodium valproate alone. Finally, Gd(DTPA)-intercalated LDH NPs were synthesized and characterized by proton (1H) nuclear magnetic resonance. The longitudinal relaxivity (r1) of 28.38 s-1 mM-1, which is over 6 times higher than the clinically approved contrast agent, Gd(DTPA), demonstrated the potential of this vector for use in magnetic resonance imaging.
Visible light-transparent single metal-semiconductor junction devices, which convert ultraviolet photon energy into high open circuit voltage (Voc>1.5-2 V), are highly desirable for transparent photovoltaics that can potentially power an electrochromic stack for smart windows. A Schottky junction solar cell, comprised of sputtered ZnO/ZnS heterojunction with Cr/Au contacts, was fabricated and an Voc of fî1.35 V was measured. Also, a low-cost route to form ZnO/ZnS heterojunctions by partial sulfurization of solution-grown ZnO thin films (350 nm-5 fÝm thick; conductivity comparable to phosphorus-doped Si) was demonstrated. A final study was on a cathode material for Li-ion batteries. Phase-pure LiFePO4 powders were synthesized by microwave-assisted sol-gel method and characterized.
ContributorsSun Zhou, Xiao Di (Author) / Dey, Sandwip K (Thesis advisor) / Krause, Stephen (Committee member) / Nagaraj, Vinay J (Committee member) / Marzke, Robert (Committee member) / Arizona State University (Publisher)
Created2014
Description
Mesoporous materials that possess large surface area, tunable pore size, and ordered structures are attractive features for many applications such as adsorption, protein separation, enzyme encapsulation and drug delivery as these materials can be tailored to host different guest molecules. Films provide a model system to understand how the pore orientation impacts the potential for loading and release of selectively sized molecules. This research work aims to develop structure-property relationships to understand how pore size, geometry, and surface hydrophobicity influence the loading and release of drug molecules. In this study, the pore size is systematically varied by incorporating pore-swelling agent of polystyrene oligomers (hPS) to soft templated mesoporous carbon films fabricated by cooperative assembly of poly(styrene-block-ethylene oxide) (SEO) with phenolic resin. To examine the impact of morphology, different compositions of amphiphilic triblock copolymer templates, poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide) (PEO-PPO-PEO), are used to form two-dimensional hexagonal and cubic mesostructures. Lastly, the carbonization temperature provides a handle to tune the hydrophobicity of the film. These mesoporous films are then utilized to understand the uptake and release of a model drug Mitoxantrone dihydrochloride from nanostructured materials. The largest pore size (6nm) mesoporous carbon based on SEO exhibits the largest uptake (3.5μg/cm2); this is attributed to presence of larger internal volume compared to the other two films. In terms of release, a controlled response is observed for all films with the highest release for the 2nm cubic film (1.45 μg/cm2) after 15 days, but this is only 56 % of the drug loaded. Additionally, the surface hydrophobicity impacts the fraction of drug release with a decrease from 78% to 43%, as the films become more hydrophobic when carbonized at higher temperatures. This work provides a model system to understand how pore morphology, size and chemistry influence the drug loading and release for potential implant applications.
ContributorsLabiano, Alpha (Author) / Vogt, Bryan (Thesis advisor) / Rege, Kaushal (Committee member) / Dai, Lenore (Committee member) / Potta, Thrimoorthy (Committee member) / Arizona State University (Publisher)
Created2011
Description
In the United States, 12% of women are typically diagnosed with breast cancer, where 20-30% of these cases are identified as Triple Negative Breast Cancer (TNBC). In the state of Arizona, 810 deaths occur due to breast cancer and more than 4,600 cases are diagnosed every year (American Cancer Society). The lack of estrogen, progesterone, and HER2 receptors in TNBC makes discovery of targeted therapies further challenging. To tackle this issue, a novel multi-component drug vehicle is presented. Previously, we have shown that mitoxantrone, a DNA damaging drug, can sensitize TNBC cells to TRAIL, which is a protein that can selectively kill cancer cells. In this current study, we have formulated aminoglycoside-derived nanoparticles (liposomes) loaded with mitoxantrone, PARP inhibitors, for delivery to cancer cells. PARP inhibitors are helpful in preventing cancer cells from repairing their DNA following damage with other drugs (e.g. mitoxantrone). Various treatment liposome groups, consisting of lipid-containing polymers (lipopolymers) synthesized in our laboratory, were formulated and characterized for their size, surface charge, and stability. PARP inhibitors and treatment of cells for in-vitro and in-vivo experiments with these liposomes resulted in synergistic death of cancer cells. Finally, studies to evaluate the pre-clinical efficacy of these approaches using immuno-deficient mouse models of TNBC disease have been initiated.
ContributorsMuralikrishnan, Harini (Author) / Rege, Kaushal (Thesis advisor) / Holechek, Susan (Committee member) / Nannenga, Brent (Committee member) / Arizona State University (Publisher)
Created2018
Description
The primary objective of this research project is to develop dual layered polymeric microparticles with a tunable delayed release profile. Poly(L-lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) phase separate in a double emulsion process due to differences in hydrophobicity, which allows for the synthesis of double-walled microparticles with a PLA shell surrounding the PLGA core. The microparticles were loaded with bovine serum albumin (BSA) and different volumes of ethanol were added to the PLA shell phase to alter the porosity and release characteristics of the BSA. Different amounts of ethanol varied the total loading percentage of the BSA, the release profile, surface morphology, size distribution, and the localization of the protein within the particles. Scanning electron microscopy images detailed the surface morphology of the different particles. Loading the particles with fluorescently tagged insulin and imaging the particles through confocal microscopy supported the localization of the protein inside the particle. The study suggest that ethanol alters the release characteristics of the loaded BSA encapsulated in the microparticles supporting the use of a polar, protic solvent as a tool for tuning the delayed release profile of biological proteins.
ContributorsFauer, Chase Alexander (Author) / Stabenfeldt, Sarah (Thesis director) / Ankeny, Casey (Committee member) / Barrett, The Honors College (Contributor) / Harrington Bioengineering Program (Contributor)
Created2015-05
Description
One of the most prominent biological challenges for the field of drug delivery is the blood-brain barrier. This physiological system blocks the entry of or actively removes almost all small molecules into the central nervous system (CNS), including many drugs that could be used to treat diseases in the CNS. Previous studies have shown that activation of the adenosine receptor signaling pathway through the use of agonists has been demonstrated to increase BBB permeability. For example, regadenoson is an adenosine A2A receptor agonist that has been shown to disrupt the BBB and allow for increased drug uptake in the CNS. The goal of this study was to verify this property of regadenoson. We hypothesized that co-administration of regadenoson with a non-brain penetrant macromolecule would facilitate its entry into the central nervous system. To test this hypothesis, healthy mice were administered regadenoson or saline concomitantly with a fluorescent dextran solution. The brain tissue was either homogenized to measure quantity of fluorescent molecule, or cryosectioned for imaging with confocal fluorescence microscopy. These experiments did not identify any significant difference in the amount of fluorescence detected in the brain after regadenoson treatment. These results contradict those of previous studies and highlight potential differences in injection methodology, time windows, and properties of brain impermeant molecules.
ContributorsWohlleb, Gregory Michael (Author) / Sirianni, Rachael (Thesis director) / Stabenfeldt, Sarah (Committee member) / Barrett, The Honors College (Contributor) / Harrington Bioengineering Program (Contributor)
Created2015-05
Description
With microspheres growing in popularity as viable systems for targeted drug therapeutics, there exist a host of diseases and pathology induced side effects which could be treated with poly(lactic-co-glycolic acid) [PLGA] microparticle systems [6,10,12]. While PLGA systems are already applied in a wide variety the clinical setting [11], microparticles still have some way to go before they are viable systems for drug delivery. One of the main reasons for this is a lack of fabrication processes and systems which produce monodisperse particles while also being feasible for industrialization [10]. This honors thesis investigates various microparticle fabrication techniques \u2014 two using mechanical agitation and one using fluid dynamics \u2014 with the long term goal of incorporating norepinephrine and adenosine into the particles for metabolic stimulatory purposes. It was found that mechanical agitation processes lead to large values for dispersity and the polydispersity index while fluid dynamics methods have the potential to create more uniform and predictable outcomes. The research concludes by needing further investigation into methods and prototype systems involving fluid dynamics methods; however, these systems yield promising results for fabricating monodisperse particles which have the potential to encapsulate a wide variety of therapeutic drugs.
ContributorsRiley, Levi Louis (Author) / Vernon, Brent (Thesis director) / VanAuker, Michael (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2018-12
Description
Locomotion of microorganisms is commonly observed in nature. Although microorganism locomotion is commonly attributed to mechanical deformation of solid appendages, in 1956 Nobel Laureate Peter Mitchell proposed that an asymmetric ion flux on a bacterium's surface could generate electric fields that drive locomotion via self-electrophoresis. Recent advances in nanofabrication have enabled the engineering of synthetic analogues, bimetallic colloidal particles, that swim due to asymmetric ion flux originally proposed by Mitchell. Bimetallic colloidal particles swim through aqueous solutions by converting chemical fuel to fluid motion through asymmetric electrochemical reactions. This dissertation presents novel bimetallic motor fabrication strategies, motor functionality, and a study of the motor collective behavior in chemical concentration gradients. Brownian dynamics simulations and experiments show that the motors exhibit chemokinesis, a motile response to chemical gradients that results in net migration and concentration of particles. Chemokinesis is typically observed in living organisms and distinct from chemotaxis in that there is no particle directional sensing. The synthetic motor chemokinesis observed in this work is due to variation in the motor's velocity and effective diffusivity as a function of the fuel and salt concentration. Static concentration fields are generated in microfluidic devices fabricated with porous walls. The development of nanoscale particles that swim autonomously and collectively in chemical concentration gradients can be leveraged for a wide range of applications such as directed drug delivery, self-healing materials, and environmental remediation.
ContributorsWheat, Philip Matthew (Author) / Posner, Jonathan D (Thesis advisor) / Phelan, Patrick (Committee member) / Chen, Kangping (Committee member) / Buttry, Daniel (Committee member) / Calhoun, Ronald (Committee member) / Arizona State University (Publisher)
Created2011
Description
The concentration necessary to kill bacterial biofilms with antimicrobials is the minimum biofilm eradication concentration (MBEC). This is usually determined using an in vitro approach and will vary within different strains of bacteria. Biomedical implants produce biofilm-related infections presenting a unique challenge due to the combination of subpopulations of the bacterial community and the polysaccharide matrix presented by biofilms. The purpose of this investigation is to determine how exposure times in the order of weeks to months affect the MBEC. Using an in vitro approach, Staphylococcus aureus (UAMS-1) and methicillin-resistant Staphylococcus aureus (MRSA) biofilms were produced with a 24 hour growth time and exposed to two antimicrobials, tobramycin and vancomycin, and one combination treatment that consisted of 1:1 tobramycin: vancomycin by weight. Crystal violet screening was used in order to ensure the integrity of the biofilm matrix throughout the full time of exposure. It was determined that UAMS-1 MBECs were lowered after 56 days of exposure than after 5 days for all three treatment groups. MRSA MBECs after 5 days of exposure decreased only with in vancomycin treatment group.
ContributorsSteinhauff, Douglas Busch (Author) / Caplan, Michael (Thesis director) / Overstreet, Derek (Committee member) / Castaneda, Paulo (Committee member) / Materials Science and Engineering Program (Contributor) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05