Poly(lactide-co-glycolide)-Hydroxyapatite Composites: The Development of Osteoinductive Scaffolds for Bone Regenerative Engineering

ABSTRACTRegenerative engineering represents a new multidisciplinary paradigm to engineer complex tissues, organs, or organ systems through the integration of tissue engineering with advanced materials science, stem cell science and developmental biology. While possessing elements of tissue engineering, regenerative medicine, and morphogenesis, regenerative engineering is distinct from these individual disciplines since it specifically focuses on the integration and subsequent response of stem cells to biomaterials. One goal of regenerative engineering is the design of materials capable of inducing associated cells toward highly specialized functions. For example, the interaction of cells with calcium phosphate surfaces has proven to be an important signaling modality in promoting osteogenic differentiation. A biodegradable polymer-ceramic composite system has been developed from poly(lactide-co-glycolide) and in situ synthesized hydroxyapatite based on the three-dimensional sintered microsphere matrix platform. We have systematically optimized scaffold physico-chemical, mechanical, and structural properties for bone tissue regeneration applications by varying several parameters such as solution pH, polymer:ceramic ratio, sintering time and sintering temperature. The bioactivity of composite scaffolds is attributed to their ability to deliver calcium ions to surrounding medium and allow for reprecipitation of calcium phosphate on the scaffold surface. Furthermore, the composite scaffolds have demonstrated increased loading capacity of osteoinductive growth factor (BMP-2) and a more sustained release profile due to a greater number of adsorption sites provided by the ionic calcium and phosphate groups as well as a larger matrix surface area. In vitro cell studies were performed to investigate the efficacy of this composite system to induce osteogenic differentiation of human adipose-derived stem cells. Cells cultured on the ceramic containing scaffolds exhibited significantly higher expression of osteoblastic markers and greater extracellular matrix mineralization than non-ceramic containing scaffolds, indicating the potential for the ceramic phase to promote osteogenic differentiation. In addition, loaded BMP-2 retained its bioactivity as a mitogen and osteoinductive agent during the differentiation of adipose-derived stem cells into mature osteoblasts. In vivo evaluation using a critical-sized ulnar defect model in New Zealand white rabbits demonstrated the ability of composite scaffolds to support cellular infiltration throughout the scaffold pore structure and vascularization of new tissue, as well as facilitate formation of newly mineralized bone tissue. The work described herein provides strong evidence for the potential of polymer-ceramic composite scaffolds to function as osteoinductive bone graft substitutes, and paves the way for future development of advanced tissue-inducing materials.