Understanding how polymer structure–property relationships control drug loading, release, degradation, and cellular interactions
Creators: name: Miles, Catherine Elizabeth
Publisher: name: No Publisher Supplied
Year: 2022

description: Advances in drug delivery platforms have improved medical care significantly over the last decades. Healthcare would not be where it is today without the development of polymeric biomaterials capable of delivering active pharmaceutical ingredients (APIs) in a controllable manner. While initial devices consisted of nondegradable polymers, advancements in polymer science led to the discovery of numerous influential polymers that are currently on the market for their use in drug delivery. Of these, poly(lactic-co-glycolic acid) (PLGA) rose to the forefront for its use in biomedical applications including drug delivery and tissue engineering. The development of micro- and nano-particle delivery systems transformed sustained release applications allowing for the delivery of APIs out to several months. However, while microparticles are easy to formulate, and offer a convenient mode of administration through injection or ingestion, they are often limited by their inherent burst release, low encapsulation efficiency, and an incomplete understanding of the molecular and mechanistic properties of the formulation.This research aims to enhance the basic understanding of how polymer structure properties impact drug loading, release, degradation, and cellular interactions; and apply this fundamental knowledge to a tissue engineering application. For these studies, a laboratory developed tyrosine-derived polymer library was used to systematically vary different physical and thermal properties and test their impact on drug release from microparticles. However, first an understanding of both hydrophilic and hydrophobic drug loading needed to be explored. Chapter 3 focuses on using a subset of the polymer library to encapsulate both hydrophilic and hydrophobic drugs into polymer microparticles in the presence of various cosolvents and as a solid suspension. Hydrophobic drugs were successfully loaded up to 50 weight percent (wt %) when loaded as a solid suspension, and by adjusting the polymer concentration during particle formation, release rates were able to be controlled. However, the microparticle formulation method used was less successful in loading hydrophilic drugs.After an optimized method of drug encapsulation was established, Chapter 4 investigates drug loading of hydrophobic corticosteroid dexamethasone into the entire library of polymers. The library was composed of different hydrophilicity, glass transition (Tg) and melting (Tm) temperatures, water miscibility, and crystallinity polymers. It is hypothesized that in the absence of polymer-drug interactions, drug release will be controlled by either the Tg of the polymer or the ability for the medium to perfuse into the particle matrix. Dexamethasone loading was high for all formulations, indicating that polymer properties do not impact drug loading when the drug is loaded as a solid suspension. Long term release studies were monitored out to 119-days and differences in release profiles were observed from the different formulations. By studying the fundamental polymer properties, it was found that when there is no polymer-drug interaction, polymer crystallite size strongly correlated with faster drug release, suggesting that larger crystallites reduce the tortuosity for dexamethasone to diffuse out of the particle matrix.In addition to the properties studied, polymer degradation plays a critical role in not only further understanding drug release rates, but also in confirming the safety of a medical device. Both the degradation mechanism and kinetics need to be well understood before a polymer can be brought into clinical trials. Degradation studies are often slow and time consuming, lasting months to several years. It is hypothesized that accelerated degradation conditions can be used to predict how a polymer will degrade under physiological conditions. Chapter 5 describes how this was tested by using a polymer containing both ester and amide functional groups and exposing the polymer to accelerated degradation conditions (temperature, organic solvent, and enzyme) and comparing the results against physiological degradation. It was found that temperature accelerated degradation conditions proceeded the fastest. When enzymes were introduced, polymer degradation to a lower molecular weight chain was needed for the enzyme active site to increase the rate of degradation. These results show the potential for accelerated degradation methods to be used to elucidate polymer degradation behavior in a more rapid time frame.Finally, Chapter 6 describes how a subset of polymers was used to study cellular interactions, both cell adhesion and proliferation. It was hypothesized that polymer rigidity and hydrophobicity will impact cell adhesion; however, after cells have attached to the polymer surface, proliferation will proceed until all available surface area has been occupied. To test this, microparticles were exposed to a selection of cell lineages at various cell densities. It was confirmed that polymer properties impact cell adhesion and polymer crystallite size and Tg were most influential. These microparticles were then studied for their use in tissue engineering. It has been shown that bone morphogenetic protein-2 (BMP-2) is a valuable growth factor capable of promoting cell differentiation towards osteoblasts. High BMP-2 loading was achieved for the particles tested and alkaline phosphatase (ALP), which is often used as an indicator of the presence of osteoblasts, was found to be present indicating that the cells had proceeded down the osteoblast lineage. The use of these polymeric microparticles brings this dissertation full circle. First, polymer microparticles were optimized for their use in drug loading. Then, an understanding of the polymer properties that effect drug release was investigated, and a thorough degradation study was carried out to develop accelerated degradation conditions to elucidate the polymer degradation mechanisms. Next, cellular interactions were studied to expand the use of these particles to in vivo applications. Finally, successful incorporation of a bone regeneration growth factor with these polymers provides a new alternative polymer for tissue regeneration applications. By measuring a diversity of polymer properties, a predictive approach can be used to select polymers with specific properties that will lead to the desired release profile or cellular interaction for the application.