Development of Synthetic Polymeric and Ceramic Composite Constructs for Bone Tissue Engineering
Smith, Brandon Tyler
Mikos, Antonios G
Doctor of Philosophy
The field of tissue engineering has developed a multitude of synthetic bone substitutes in order to mitigate the drawbacks associated with grafts. However, achieving complete regeneration of large tissue defects by utilizing synthetic substitutes continues to present many obstacles to tissue engineers. Because bone is a complex tissue that has an elaborate architecture which has regional differences in structure and composition we sought to develop biomaterials that combine biocompatible ceramics and synthetic polymers that can better recapitulate the complex architecture and composition present in native bone. In this thesis, we seek to develop bone tissue engineering strategies that leverage ceramics and synthetic polymers. First, we fabricated and characterized glucose microparticles (GMPs) to serve as a porogen within calcium phosphate cements (CPCs). In the first specific aim we demonstrate one can easily tailor the handling properties and overall macroporosity by altering the concentration of GMPs within CPCs. Furthermore, after 3 days, GMPs were completely dissolved further increasing the scaffolds macroporosity. The second objective of this work was to evaluate regenerative efficacy of GMP loaded CPCs in vivo using a rat femoral condyle defect model. Constructs that incorporated smaller GMPs were found to increase the amount of regenerated bone after 2 weeks compared to CPC controls. The results of this study demonstrated the ability of a simple metabolically active molecule to improve bone formation in CPC based biomaterials. In the second Specific Aim, we investigated the effects of incorporating GMPs (developed in Specific Aim 1) and poly(lactic-co-glycolic acid) microparticles (PLGA MPs) within CPCs on the cement’s handling properties and physicochemical properties. By analyzing the molecular weights of PLGA MPs, we demonstrated that GMPs can be leveraged to impede the local acidity created due to the degradation of PLGA MPs by increasing the scaffold porosity to facilitate the diffusion of lactic and glycolic acid degradation products to the surrounding media, thus allowing better control of the PLGA degradation kinetics. Finally, the last aim of this dissertation leveraged 3D printing for the fabrication of multiphasic ceramic/polymer composites in order to guide mesenchymal stem cell differentiation. We demonstrated that one can dramatically affect the osteogenic differentiation of mesenchymal stem cells by altering the porosity, ceramic content, and concentration. In summary, the overall objective of this project is to develop tissue engineering strategies that leverage both ceramics and synthetic polymers. During the course of this thesis, we will demonstrate that simple metabolically active molecules can serve as an innovative porogen for calcium phosphate cements and that ceramic content, concentration and scaffold porosity can be tailored to control the phenotype of mesenchymal stem cells within 3D constructs.
tissue engineering; bioengineering; biomaterials; orthopedic; 3D printing