The long-term objective of this research is to study bone ingrowth into synthetic biodegradable osteoinductive scaffolds for reconstruction of craniofacial defects. Since bone morphogenetic proteins (BMPs) signaling is highly regulated, the graft has to be loaded with doses of 4-5 orders of magnitude (with adverse side effects) higher than the amount found endogenously. An attractive alternative is to use peptides, based on the active domains of BMPs to initiate the cascade of osteogenesis. The strategy involves covalent attachment of an osteoinductive azide-functionalized """"""""BMP peptide"""""""", corresponding to amino acid residues 73-92 of the recombinant human bone morphogenetic protein-2 (rhBMP-2), to a novel bioresorbable poly(lactide-co-glycolide fumarate) (PLGF) scaffold. The short lactide-co-glycolide chains in PLGF impart degradability to the macromer while the fumarate units provide sites for crosslinking for structural support. We hypothesized that the crosslinked scaffold provides structural support to the regenerating region and induces osteogenesis by the interaction of migrating bone marrow stromal (BMS) cells with the grafted BMP peptide. Moreover, the scaffold will degrade concurrent with the production of mineralized matrix to increase bone volume.
The aim of this proposal is to determine osteoinductivity and the extent of bone formation of BMP peptide grafted PLGF scaffold in-vitro and in-vivo. In the first part of Aim 1, the effect of PLGF composition and scaffold porosity on degradation characteristics and mechanical strength will be determined. The outcome of Aim 1.1 is the best lactide: glycolide ratio of PLGF and best porosity of the scaffold. In the second part of Aim 1, effect of BMP peptide grafted PLGF on differentiation and mineralization of BMS cells will be determined in-vitro. The outcome of Aim 1.2, is the best density of BMP peptide grafted to PLGF scaffold, as judged by the highest mineral content.
In Aim 2, we will determine the effect of BMP peptide grafted scaffold on bone formation in critical-size rat cranial defect in-vivo. Experimental groups will include scaffolds grafted with mutant BMP peptide (negative control), BMP peptide (experimental group), and scaffolds with rhBMP-2 protein (positive control). Success will be judged by the continuous bridging of new bone across the scaffold and by bone mineral density.

Public Health Relevance

Over twenty million people in USA are totally edentulous and about half a million children worldwide are born annually with congenital craniofacial deformities. Degradable biomaterials that are space occupying, osteoinductive, have the consistency to protect the defect from soft tissue collapse, and degrade concurrent with the formation of new extra-cellular matrix to increase bone volume have the potential for breakthroughs in the development of adaptable scaffolds to the changing craniofacial defect.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Small Research Grants (R03)
Project #
5R03DE019180-02
Application #
7790647
Study Section
NIDCR Special Grants Review Committee (DSR)
Program Officer
Drummond, James
Project Start
2009-04-01
Project End
2011-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
2
Fiscal Year
2010
Total Cost
$106,920
Indirect Cost
Name
University of South Carolina at Columbia
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
041387846
City
Columbia
State
SC
Country
United States
Zip Code
29208
Karaman, Ozan; Kumar, Ankur; Moeinzadeh, Seyedsina et al. (2016) Effect of surface modification of nanofibres with glutamic acid peptide on calcium phosphate nucleation and osteogenic differentiation of marrow stromal cells. J Tissue Eng Regen Med 10:E132-46
Moeinzadeh, Seyedsina; Barati, Danial; Sarvestani, Samaneh K et al. (2015) Experimental and computational investigation of the effect of hydrophobicity on aggregation and osteoinductive potential of BMP-2-derived peptide in a hydrogel matrix. Tissue Eng Part A 21:134-46
Mercado, Angel E; Yang, Xiaoming; He, Xuezhong et al. (2014) Effect of grafting BMP2-derived peptide to nanoparticles on osteogenic and vasculogenic expression of stromal cells. J Tissue Eng Regen Med 8:15-28
Jabbari, Esmaiel (2013) Osteogenic peptides in bone regeneration. Curr Pharm Des 19:3391-402
Moeinzadeh, Seyedsina; Barati, Danial; Sarvestani, Samaneh K et al. (2013) Nanostructure formation and transition from surface to bulk degradation in polyethylene glycol gels chain-extended with short hydroxy acid segments. Biomacromolecules 14:2917-28
Yang, Xiaoming; Sarvestani, Samaneh K; Moeinzadeh, Seyedsina et al. (2013) Effect of CD44 binding peptide conjugated to an engineered inert matrix on maintenance of breast cancer stem cells and tumorsphere formation. PLoS One 8:e59147
Jabbari, Esmaiel; Yang, Xiaoming; Moeinzadeh, Seyedsina et al. (2013) Drug release kinetics, cell uptake, and tumor toxicity of hybrid VVVVVVKK peptide-assembled polylactide nanoparticles. Eur J Pharm Biopharm 84:49-62
Yang, Xiaoming; Sarvestani, Samaneh K; Moeinzadeh, Seyedsina et al. (2013) Three-dimensional-engineered matrix to study cancer stem cells and tumorsphere formation: effect of matrix modulus. Tissue Eng Part A 19:669-84
Moeinzadeh, Seyedsina; Barati, Danial; He, Xuezhong et al. (2012) Gelation characteristics and osteogenic differentiation of stromal cells in inert hydrolytically degradable micellar polyethylene glycol hydrogels. Biomacromolecules 13:2073-86
He, Xuezhong; Yang, Xiaoming; Jabbari, Esmaiel (2012) Combined effect of osteopontin and BMP-2 derived peptides grafted to an adhesive hydrogel on osteogenic and vasculogenic differentiation of marrow stromal cells. Langmuir 28:5387-97

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