Matching Items (51)
Description
Achieving effective drug concentrations within the central nervous system (CNS) remains one of the greatest challenges for the treatment of brain tumors. The presence of the blood-brain barrier and blood-spinal cord barrier severely restricts the blood-to-CNS entry of nearly all systemically administered therapeutics, often leading to the development of peripheral toxicities before a treatment benefit is observed. To circumvent systemic barriers, intrathecal (IT) injection of therapeutics directly into the cerebrospinal fluid (CSF) surrounding the brain and spinal cord has been used as an alternative administration route; however, its widespread translation to the clinic has been hindered by poor drug pharmacokinetics (PK), including rapid clearance, inadequate distribution, as well as toxicity. One strategy to overcome the limitations of free drug PK and improve drug efficacy is to encapsulate drug within nanoparticles (NP), which solubilize hydrophobic molecules for sustained release in physiological environments. In this thesis, we will develop NP delivery strategies for brain tumor therapy in two model systems: glioblastoma (GBM), the most common and deadly malignant primary brain tumor, and medulloblastoma, the most common pediatric brain tumor. In the first research chapter, we developed 120 nm poly(lactic acid-co-glycolic acid) NPs encapsulating the chemotherapy, camptothecin, for intravenous delivery to GBM. NP encapsulation of camptothecin was shown to reduce the drug’s toxicity and enable effective delivery to orthotopic GBM. To build off the success of intravenous NP, the second research chapter explored the utility of 100 nm PEGylated NPs for use with IT administration. Using in vivo imaging and ex vivo tissue slices, we found the NPs were rapidly transported by the convective forces of the CSF along the entire neuraxis and were retained for over 3 weeks. Based on their wide spread delivery and prolonged circulation, we examine the ability of the NPs to localize with tumor lesions in a leptomeningeal metastasis (LM) model of medulloblastoma. NPs administered to LM bearing mice were shown to penetrate into LM mets seeded within the meninges around the brain. These data show the potential to translate our success with intravenous NPs for GBM to improve IT chemotherapy delivery to LM.
ContributorsHouseholder, Kyle Thomas (Author) / Sirianni, Rachael W. (Thesis advisor) / Stabenfeldt, Sarah (Committee member) / Vernon, Brent (Committee member) / Caplan, Michael (Committee member) / Wechsler-Reya, Robert (Committee member) / Arizona State University (Publisher)
Created2018
Description
Rapid intraoperative diagnosis of brain tumors is of great importance for planning treatment and guiding the surgeon about the extent of resection. Currently, the standard for the preliminary intraoperative tissue analysis is frozen section biopsy that has major limitations such as tissue freezing and cutting artifacts, sampling errors, lack of immediate interaction between the pathologist and the surgeon, and time consuming.
Handheld, portable confocal laser endomicroscopy (CLE) is being explored in neurosurgery for its ability to image histopathological features of tissue at cellular resolution in real time during brain tumor surgery. Over the course of examination of the surgical tumor resection, hundreds to thousands of images may be collected. The high number of images requires significant time and storage load for subsequent reviewing, which motivated several research groups to employ deep convolutional neural networks (DCNNs) to improve its utility during surgery. DCNNs have proven to be useful in natural and medical image analysis tasks such as classification, object detection, and image segmentation.
This thesis proposes using DCNNs for analyzing CLE images of brain tumors. Particularly, it explores the practicality of DCNNs in three main tasks. First, off-the shelf DCNNs were used to classify images into diagnostic and non-diagnostic. Further experiments showed that both ensemble modeling and transfer learning improved the classifier’s accuracy in evaluating the diagnostic quality of new images at test stage. Second, a weakly-supervised learning pipeline was developed for localizing key features of diagnostic CLE images from gliomas. Third, image style transfer was used to improve the diagnostic quality of CLE images from glioma tumors by transforming the histology patterns in CLE images of fluorescein sodium-stained tissue into the ones in conventional hematoxylin and eosin-stained tissue slides.
These studies suggest that DCNNs are opted for analysis of CLE images. They may assist surgeons in sorting out the non-diagnostic images, highlighting the key regions and enhancing their appearance through pattern transformation in real time. With recent advances in deep learning such as generative adversarial networks and semi-supervised learning, new research directions need to be followed to discover more promises of DCNNs in CLE image analysis.
Handheld, portable confocal laser endomicroscopy (CLE) is being explored in neurosurgery for its ability to image histopathological features of tissue at cellular resolution in real time during brain tumor surgery. Over the course of examination of the surgical tumor resection, hundreds to thousands of images may be collected. The high number of images requires significant time and storage load for subsequent reviewing, which motivated several research groups to employ deep convolutional neural networks (DCNNs) to improve its utility during surgery. DCNNs have proven to be useful in natural and medical image analysis tasks such as classification, object detection, and image segmentation.
This thesis proposes using DCNNs for analyzing CLE images of brain tumors. Particularly, it explores the practicality of DCNNs in three main tasks. First, off-the shelf DCNNs were used to classify images into diagnostic and non-diagnostic. Further experiments showed that both ensemble modeling and transfer learning improved the classifier’s accuracy in evaluating the diagnostic quality of new images at test stage. Second, a weakly-supervised learning pipeline was developed for localizing key features of diagnostic CLE images from gliomas. Third, image style transfer was used to improve the diagnostic quality of CLE images from glioma tumors by transforming the histology patterns in CLE images of fluorescein sodium-stained tissue into the ones in conventional hematoxylin and eosin-stained tissue slides.
These studies suggest that DCNNs are opted for analysis of CLE images. They may assist surgeons in sorting out the non-diagnostic images, highlighting the key regions and enhancing their appearance through pattern transformation in real time. With recent advances in deep learning such as generative adversarial networks and semi-supervised learning, new research directions need to be followed to discover more promises of DCNNs in CLE image analysis.
ContributorsIzady Yazdanabadi, Mohammadhassan (Author) / Preul, Mark (Thesis advisor) / Yang, Yezhou (Thesis advisor) / Nakaji, Peter (Committee member) / Vernon, Brent (Committee member) / Arizona State University (Publisher)
Created2019
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
With an increased demand for more enzyme-sensitive, bioresorbable and more biodegradable polymers, various studies of copolymers have been developed. Polymers are widely used in various applications of biomedical engineering such as in tissue engineering, drug delivery and wound healing. Depending on the conditions in which polymers are used, they are modified to accommodate a specific need. For instance, polymers used in drug delivery are more efficient if they are biodegradable. This ensures that the delivery system does not remain in the body after releasing the drug. It is therefore crucial that the polymer used in the drug system possess biodegradable properties. Such modification can be done in different ways including the use of peptides to make copolymers that will degrade in the presence of enzymes. In this work, we studied the effect of a polypeptide GAPGLL on the polymer NIPAAm and compare with the previously studied Poly(NIPAAm-co-GAPGLF). Both copolymers Poly(NIPAAm-co-GAPGLL) were first synthesized from Poly(NIPAAm-co-NASI) through nucleophilic substitution by the two peptides. The synthesis of these copolymers was confirmed by 1H NMR spectra and through cloud point measurement, the corresponding LCST was determined. Both copolymers were degraded by collagenase enzyme at 25 ° C and their 1H NMR spectra confirmed this process. Both copolymers were cleaved by collagenase, leading to an increase in solubility which yielded a higher LCST compared to before enzyme degradation. Future studies will focus on evaluating other peptides and also using other techniques such as Differential Scanning Microcalorimetry (DSC) to better observe the LCST behavior. Moreover, enzyme kinetics studies is also crucial to evaluate how fast the enzyme degrades each of the copolymers.
ContributorsUwiringiyimana, Mahoro Marie Chantal (Author) / Vernon, Brent (Thesis director) / Nikkhah, Mehdi (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
This report provides information concerning qualities of methylcellulose and how those properties affect further experimentation within the biomedical world. Utilizing the compound’s biocompatibility many issues, ranging from surgical to cosmetic, can be solved. As of recent, studies indicate, methylcellulose has been used as a physically cross-linked gel, which cannot sustain a solid form within the body. Therefore, this report will ultimately explore the means of creating a non-degradable, injectable, chemically cross-linking methylcellulose- based hydrogel. Methylcellulose will be evaluated and altered in experiments conducted within this report and a chemical cross-linker, developed from Jeffamine ED 2003 (O,O′-Bis(2-aminopropyl) polypropylene glycol-block-polyethylene glycol-block-polypropylene glycol), will be created. Experimentation with these elements is outlined here, and will ultimately prompt future revisions and analysis.
ContributorsBundalo, Zoran Luka (Author) / Vernon, Brent (Thesis director) / LaBelle, Jeffrey (Committee member) / Overstreet, Derek (Committee member) / Barrett, The Honors College (Contributor) / Harrington Bioengineering Program (Contributor)
Created2013-05
Description
Revision hip procedures represent a large financial burden on hospitals and the problem will continue to worsen as the baby boomer generation ages and life expectancy goes up. The future problem is a complex issue that bridges scientific and anecdotal evidence and must be solved. A review of the current total hip arthroplasty procedure in regards to the physical properties of the materials used for hip prostheses is given. Revision procedures can be caused by infection or basic wear and tear from the stress that that implant is subjected to daily. Infections on these implants often present themselves as medical biofilms. The mechanisms of biofilm formation include a complex system of enzymes that work to initiate a phenotypic response based on an established quorum sensing within the colony of bacteria. Surgical methods to treat infection include irrigation and debridement as well as loading drug cement spacers with antimicrobial in hopes of delivering the antibiotic locally. Research is being done to better model the transport of drug through the tissue surrounding the implant, and will hopefully one day be available for use in individual patients.
ContributorsMcDermand, Matthew Paul (Author) / Caplan, Michael (Thesis director) / Vernon, Brent (Committee member) / McLemore, Ryan (Committee member) / Barrett, The Honors College (Contributor)
Created2013-05
Description
Cerebral aneurysms, also known as intracranial aneurysms, are sac-like lesions in the arteries of the brain that can rupture to cause subarachnoid hemorrhaging, damaging and killing brain cells. Metal coil embolization has been traditionally used to occlude and treat cerebral aneurysms to limited success, but polymer embolization has been suggested, because it can provide a greater fraction of occlusion. One such polymer with low cytotoxicity is poly(propylene glycol)diacrylate (PPODA) crosslinked via Michael-type addition with pentaerythritol tetrakis(3-mercaptopropionate) (QT). This study was performed to examine the behavior of PPODA-QT gel in vitro under pulsatile flow emulating physiological conditions. An idealized cerebral aneurysm flow model was designed based on geometries associated with an increase in rupture risk. Pressure was monitored at the apex of the aneurysm dome for varied flow rates and polymer filling fractions of 32.4, 78.2, and 100%. The results indicate that the amount of PPODA-QT deployed into the aneurysm decreases the peak-to-peak oscillation in pressure at the aneurysm wall by an inverse proportion. The 32.4 and 78.2% treatments did not significantly decrease the mean pressure applied to the aneurysm dome, but the 100% treatment greatly reduced it by diverting flow. This study indicates that the maximum filling fraction after swelling of PPODA-QT polymer should be deployed into the aneurysmal sac for treatment.
ContributorsWorkman, Christopher David (Author) / Vernon, Brent (Thesis director) / Frakes, David (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor) / Harrington Bioengineering Program (Contributor)
Created2014-05
Description
Biofilm derived orthopedic infections are increasingly common after contamination of an open bone fracture or the surgical site pre- and post-orthopedic prosthetic insertion or removal. These infections are usually difficult to eradicate due to the resistant nature of biofilms to antimicrobial therapy. Difficulty of treatment of biofilm derived infections is also partly due to the presence of persister cells in the biofilm matrix. Persister cells are tolerant to antimicrobial therapy delivered via the systemic route. It is thus possible for these cells to repopulate their environment once systemic antimicrobial delivery is discontinued. The antimicrobial concentration required to eradicate bacterial biofilms, minimum biofilm eradication concentration (MBEC), can be determined in vitro by exposing biofilms to different regimens of antimicrobial solutions. Previous studies have demonstrated that values of the MBEC vary depending on the material and surface the biofilm grows on. This study investigated the relationship between antimicrobial susceptibility and antimicrobial exposure time, and the effects of surface material type on the antimicrobial susceptibility of staphylococcal biofilms. It was concluded that antimicrobial susceptibility increases with increased antimicrobial exposure time, and that the investigated surface and material properties did not have an effect on the susceptibility of staphylococcal biofilms to antimicrobial therapy. Further investigation is however necessary to confirm these results due to some inconsistent data obtained over the course of the trials.
ContributorsTavaziva, Gamuchirai Clinton (Author) / Vernon, Brent (Thesis director) / Overstreet, Derek (Committee member) / Castaneda, Paulo (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
Description
A self-stirring syringe pump was created in order to fill a void in the market for a medical device that could perform a lengthy drug infusion. This was accomplished by using a magnetic field mechanism that enclosed the body of a syringe. A stator was created in order to facilitate the induction of magnetic fields around the syringe body. A flexible magnetic stir bar was created to rotate within the syringe body while also being able to conform to the syringe plunder as an infusion occurred. In order for the stator with the syringe to fit onto a conventional syringe pump, a mount had to be made. This mount was removable to ensure easy access to the syringe once an infusion had occurred. A study was performed to determine whether or not the self-stirring syringe pump could keep a suspension homogenous over a lengthy infusion. It was found that the self-stirring syringe pump was able to accomplish this task.
ContributorsWitting, Avery Amadeus (Author) / Vernon, Brent (Thesis director) / Goryll, Michael (Committee member) / Faigel, Douglas (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
Cardiac tissue engineering has major applications in regenerative medicine, disease modeling and fundamental biological studies. Despite the significance, numerous questions still need to be explored to enhance the functionalities of the engineered tissue substitutes. In this study, three dimensional (3D) cardiac micro-tissues were developed through encapsulating co-culture of cardiomyocytes and cardiac fibroblasts, as the main cellular components of native myocardium, within photocrosslinkable gelatin-based hydrogels. Different co-culture ratios were assessed to optimize the functional properties of constructs. The geometry of the micro-tissues was precisely controlled using micro-patterning techniques in order to evaluate their role on synchronous contraction of the cells. Cardiomyocytes exhibited a native-like phenotype when co-cultured with cardiac fibroblasts as compared to the mono-culture condition. Particularly, elongated F-actin fibers with abundance of sarcomeric α-actinin and troponin-I were observed within all layers of the hydrogel constructs. Higher expressions of connexin-43 and integrin β1 indicated improved cell-cell and cell-matrix interactions. Amongst co-culture conditions, 2:1 (cardiomyocytes: cardiac fibroblasts) ratio exhibited enhanced functionalities, whereas decreasing the construct size adversely affected the synchronous contraction of the cells. Therefore, this study indicated that cell-cell ratio as well as the geometrical features of the micropatterned constructs are among crucial parameters, which need to be optimized in order to enhance the functionalities of engineered tissue substitutes and cardiac patches.
ContributorsSaini, Harpinder (Author) / Nikkhah, Mehdi (Thesis advisor) / Vernon, Brent (Committee member) / Towe, Bruce (Committee member) / Arizona State University (Publisher)
Created2015