Biodegradable Colloidal Gels as Malleable Tissue Scaffolds and Injectable Drug Carriers

Abstract

Repair of skeletal defects resulting from traumatic insult, tumor ablation, or congenital deformities remains a formidable challenge for clinicians. From a clinical perspective, the use of injectable materials is an attractive alternative to surgery as it reduces the risk of infection, scar formation, patient discomfort and the cost of treatment. Particularly, injectable scaffolds injected or extruded at low viscosity may be ideal scaffolds for bone repair or for delivery of drugs or cells to injured tissue. Such an approach is minimally invasive and is capable of filling complex 3D defects of irregular size and shape, but achieving a desirable injectable material for these defects is challenging. Nanotechnology, systems at sizes generally ranging between 1 and 1000 nm, is expected to have an important impact on all industries including semiconductors, manufacturing, pharmaceutics, and biotechnology. Colloidals are a nanostructured system in which the dispersed phase is so small that gravitational force is negligible and interactions are dominated by short-range and temporary forces, such as van der Waals force, electrostatic force, and/or steric force. The unique properties of high concentration, cohesive colloidal gels investigated here make it a potential candidate for injectable filler to repair bone, such as cranial defects. The objective of this thesis is to use oppositely-charged poly (D,L-lactic-co-glycolic acid) (PLGA) nanoparticles to create a novel cohesive colloidal gel. The relationship between composition of the gels and bulk properties has been explored. Oppositely-charged colloids self-assembled through interparticle interactions resulting in a stable 3-D network that was easily molded to the desired shape. Rheological tests on colloidal gels showed shear-thinning behavior and reversibility, in that viscosity was recovered. Cell seeding and viability tests with human umbilical cord mesenchymal stem cells (HUCMSCs) indicated excellent biocompatibility with these cells. Drug release from dexamethasone (DEX) loaded colloidal gels followed near-zero order kinetics over two months. These materials were also implanted in rats and histological and histochemical analyses confirmed that the PLGA colloidal gels stimulated bone formation in rat cranial bone defects. This thesis reports PLGA colloidal gels as novel injectable drug-loaded fillers desirable for promoting reconstruction and regeneration of cranial defects. Similar systems can also be utilized with extended applications in other areas, including repairing different tissue defects and providing long-term, local drug delivery.