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Parathyroid hormone effects on marrow stromal cells for potential bone regeneration applications : delivery systems development and biological characterization

University of British Columbia

Despite the inherent ability of bone tissue to regenerate upon damage, there are incidences such as ‘critical’ defects where the damaged and lost bone will not repair or regenerate itself. Thus, the natural bone regeneration process must be augmented with the application of therapeutic agents (growth factors, hormones, cells). In addition, in every possible scenario where surgical interventions are performed, there exists the risk of infections that must be minimized and managed with the administration of antibiotics. The overall goals of this thesis were to engineer, develop, and characterize biodegradable and bioresorbable polymeric microsphere and porous scaffold delivery systems for parathyroid hormone (PTH) and marrow stromal cells (MSC5), respectively, for enhancing the innate regenerative capacity of bone, and to investigate the effects of continuous and pulsatile PTH treatments on MSCs to better understand its regulatory actions on MSC differentiation, proliferation and clonogenicity. In addition, the development and characterization of biodegradable and bioresorbable polymeric microsphere delivery systems for the antibiotic, fusidic acid (FA) for potential localized application in bone infection were also undertaken. PTH-loaded poly(lactic-co-glycolic acid) (PLGA) and poly(hydroxybutyrate-co hydroxyvalerate) (PHBV) microspheres were developed. However, these initial formulations did not achieve the precise level of controlled release of PTH required for MSCs. Osteogenic differentiation of MSCs was found to increase with continuous PTH treatment, and decrease with pulsatile PTH exposure. The observed effects of PTH were strongly dependent on the presence of dexamethasone. PTH treatments did not influence MSC proliferation but was found to increase the colony forming unit-fibroblast (CFU-F) content within MSC cultures. Biocompatible, biodegradable and bioresorbable porous gelatin-alginate scaffolds produced by microwave vacuum drying were found to support MSC attachment, proliferation and differentiation. However, MSC differentiation (osteogenic, chondrogenic, adipogenic) were suppressed in vivo compared to in vitro when seeded on these scaffolds. In the process of formulating FA-loaded PLGA and PHBV microspheres, an interesting phase separation phenomenon of FA in PLGA but not in PHBV polymer was observed. Phase separated FA formed distinct, large, completely amorphous, spherical FA-rich solid microdomains throughout the PLGA microsphere, and on the microsphere surface. FA release kinetics from the microsphere formulations were controlled by selective formulation factors determined from factorial design experiments. Thus, the data presented in this thesis contribute to our understanding of PTH effects on MSCs, the responses of MSCs on porous gelatin-alginate scaffolds as well as the solid-state characteristics and release of FA loaded in PLGA and PHBV microspheres.

Thesis/Dissertation

application/pdf

2009-11-27

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/15882

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/