Development of Injectable, Stimuli-Responsive Biomaterials as Active Scaffolds for Applications in Advanced Drug Delivery and Osteochondral Tissue Regeneration.

摘要

Osteoarthritis (OA) is a degenerative joint disease that occurs when the cartilage matrix begins to breakdown. Every year, over 3.1 million surgeries are performed in an effort to treat damaged cartilage tissue. Current treatment options such as osteochondral tissue grafting, micro-fracturing, and total knee replacements (TKRs) are effective in alleviating symptoms associated with OA, but often fail to promote the regeneration of normal cartilage. Therefore, due to the limitations of the current treatment options available, it has become necessary to develop better medical solutions to restore or regenerate cartilage tissue previously damaged by OA.;Stimuli-responsive hydrogels, capable of exhibiting dramatic changes in swelling behavior, network structure, permeability and mechanical strength in response to changes in their local environment, have emerged as potential candidates as active scaffolds for several tissue engineering applications. Magneto-responsive biomaterials have become a subject of interest in the field of tissue engineering as their physical and structural properties could be manipulated spatiotemporally by varying the magnetic field strength, making them useful for applications in advanced drug delivery and osteochondral tissue regeneration. Thus, the goal of this thesis was to investigate the feasibility of developing an injectable, magneto-responsive hydrogel scaffold capable of delivering viable stem cell populations to a cartilage defect, and to spatiotemporally control the regeneration of the cartilage tissue in vivo..;A magneto-responsive biomaterial was made by adding functional paramagnetic iron (III) oxide Fe3O4 nanoparticles into a thermosensitive pNiPAAm-based hydrogel with degradable PAMAM-based crosslinking macromers. From our tangential force measurements, we were able to determine that, under a low magnetic field of 0.3 tesla, physiologically-relevant engineering stresses of 52.5 Pa and 29.6 Pa were generated for hydrogels with 625 mug/mL of 50 or 500 nm nanoparticles (NPs), respectively. Furthermore, primary Mesenchymal Stem Cells (MSCs) were encapsulated within the nanocomposite hydrogel up to seven days, showing that the inclusion of the nanoparticles had no significant impact on MSC viability. These results show that these magnetic hydrogels could be used as injectable scaffolds that permit real-time spatiotemporal control of deformation of the hydrogel, leading to the physical stimulation of encapsulated cells.;Next, to increase macro-porosity within the scaffold, degradable gelatin micro-particles were added to the magnetic hydrogel formulation. Addition of the micro-particles had no adverse effect on cellularity, gelation kinetics or hydrogel formation. However, the micro-particles did have a diminishing effect on the magnetic saturation of our magneto-responsive hydrogels. Furthermore, the feasibility of using magnetic field to accelerate the release of a therapeutic agent from the GMP-composite magnetic hydrogels was investigated.;Finally, the effects of short term magnetic stimulation on stem cell differentiation were also explored. Results showed that magnetic stimulation increases cellularity and hydrogel calcification increased with increases in NP loading but decreased with increases in magnetic stimulation. Furthermore, Alkaline Phosphatase (ALP) expression increased with NP loading, but decreased with magnetic stimulation. It is our hope is that the results presented in this thesis would encourage other scientists to explore using novel stimuli-responsive biomaterials to restore severely damaged tissues.