Engineering Bone Formation in Multi-Functional Nanocomposite Scaffolds

University South Carolina Research Foundation, Columbia SC

Investigators

Abstract

CBET-0756394 Jabbari In the natural process of bone regeneration, the extracellular matrix protects the regenerating region from soft tissue collapse and provides multiple signals to the migrating cells to guide the cascade of migration, matrix degradation and invasion, and morphogenesis. An engineered scaffold should mimic the complexity of the bone extracellular matrix by providing temporary structural support, degrade concurrent with cell migration to increase free volume for new matrix formation, and provide sites for cell adhesion and proliferation. It is hypothesized that a composite scaffold crosslinked with a functionalized peptide that has multiple covalently-linked active domains can coordinate multiple regenerative functions, mimicking the natural signaling cascade leading to bone morphogenesis. With this hypothesis in mind, the objective of this project is to determine the effects of a peptide with multiple bioactive domains consisting of a domain that binds to apatite nanoparticles, a matrix metalloproteinase (MMP) degradable domain, and an integrin-binding RGD domain on temporary structural support, matrix degradation concurrent with cell migration, and cell adhesion and proliferation, respectively. The multi-domain peptide will covalently link the hydrogel phase to the inorganic nanoapatite phase to form a multi-functional composite scaffold. Three tasks are proposed to demonstrate the proof-of-concept: First, a molecular model will be used to predict the viscoelastic response of the nanocomposite and to find the effective range of concentrations of the apatite nanoparticles, multi-functional apatite-binding peptide, and the MMP degradable peptide crosslinker. Second, the ability of the composite scaffold to modulate cell migration to scaffold degradation will be determined in-vitro with bone marrow stromal (BMS) cells. Third, the effect of the nanocomposite matrix on osteogenesis/vasculogenesis and mineralized matrix production will be determined in-vitro by seeding with BMS cells and in-vivo by implantation in the rat calvarial defect model. The broader impact of this work lies in the application of these ideas to areas other than skeletal tissue regeneration, like dental restoration, osteoarthritis and cartilage regeneration, treatment of degenerative disk disease, replacement of heart valves, targeted peptidomimetic drug delivery systems, and in developing substrates for concurrent differentiation of progenitor cells to multiple lineages. A broad educational component is part of this project, wherein graduate and undergraduate students will benefit from the overall research approach, which integrates materials science and engineering, biochemistry, molecular and cell biology, and orthopedics to design scaffolds for tissue regeneration. As part of the outreach program, a high school student is selected each summer to participate in research related to tissue engineering.