Mapping Microclimate pH in Biodegradable Polymeric Microspheres.
dc.contributor.author | Liu, Yajun | en_US |
dc.date.accessioned | 2013-09-24T16:03:07Z | |
dc.date.available | NO_RESTRICTION | en_US |
dc.date.available | 2013-09-24T16:03:07Z | |
dc.date.issued | 2013 | en_US |
dc.date.submitted | 2013 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/99989 | |
dc.description.abstract | The microclimate inside microspheres prepared from biodegradable polymers (e.g., poly(lactic-co-glycolic acid) PLGA) often becomes acidic owing to the accumulation of water-soluble polymer degradation products, which can induce the destablization of encapsulated therapeutic agents. The objective of this dissertation was to quantitatively evaluate the microclimate pH (μpH) inside biodegradable polymeric microspheres in order to facilitate the development of microsphere formulations that control μpH and stabilize acid-labile drugs. Chapter 1 presents an overview of the background of these studies with a focus on the most common biodegradable polymer, PLGA. In Chapter 2, the μpH distribution inside protein-encapsulated PLGA microspheres was accurately quantified using a ratiometric method based on confocal laser scanning microscopy (CLSM). The fluorescent response of Lysosensor yellow/blue® dextran used to map acidic µpH in PLGA was influenced by the presence of encapsulated protein. A method for correction of the interference of protein was developed and validated. The µpH kinetics in four different PLGA microsphere formulations during incubation under physiological conditions were determined to be roughly pH 4 to neutral pH depending on the formulation. Based on previous literature findings of enhanced stability of encapsulated proteins and peptides in hydrophilic and biodegradable poly(lactic-co-hydroxymethyl glycolic acid) (PLHMGA) microspheres, the μpH distribution and kinetics in the microspheres prepared from PLHMGAs were evaluated in Chapter 3 by CLSM and compared that with their PLGA counterparts. The PLHMGA microspheres developed a far more neutral μpH than PLGA, which was linked to more rapid diffusion of acidic degradation products out of the polymer. In the last chapter, a mathematical model was developed to simulate the μpH kinetics and spatial distribution inside degrading PLGA microspheres by considering the acid production, mass transfer via diffusion and partition of water-soluble acids that contribute to the development of μpH. Fundamental parameters in the PLGA microspheres were determined from experiments to validate the model. The model successfully predicted the kinetics of μpH development, whereas showing a small difference in distribution compared to experimental results. Hence, these mechanistic approaches may provide valuable experimental and theoretical tools to control μpH inside the most commonly used biodegradable polymer for controlled release of acid-labile therapeutics. | en_US |
dc.language.iso | en_US | en_US |
dc.subject | Microclimate PH | en_US |
dc.subject | Poly(Lactic-co-Glycolic) Acid | en_US |
dc.subject | Poly(Lactide-co-Hydroxymethyl Glycolide) | en_US |
dc.subject | Biodegradable Microspheres | en_US |
dc.subject | Confocal Laser Scanning Microscopy | en_US |
dc.subject | PH Simulation | en_US |
dc.title | Mapping Microclimate pH in Biodegradable Polymeric Microspheres. | en_US |
dc.type | Thesis | en_US |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Pharmaceutical Sciences | en_US |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | en_US |
dc.contributor.committeemember | Schwendeman, Steven P. | en_US |
dc.contributor.committeemember | Meyerhoff, Mark E. | en_US |
dc.contributor.committeemember | Amidon, Gregory E. | en_US |
dc.contributor.committeemember | Rodriguez-Hornedo, Nair | en_US |
dc.subject.hlbsecondlevel | Pharmacy and Pharmacology | en_US |
dc.subject.hlbtoplevel | Health Sciences | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/99989/1/yajunl_1.pdf | |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
Files in this item
Remediation of Harmful Language
The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.
Accessibility
If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.