According to the National Institute of Dental and Craniofacial Research, 86% of adults over 70 years of age have at least moderate periodontitis with over a quarter having lost their teeth, resulting in serious health and quality of life repercussions. Bone grafting is routinely necessary prior to the placement of Dental implants due to bone loss caused by periodontitis. Autograft bone is considered the gold standard because of its osteogenic cells, osteoinductive factors, and osteoconductive properties. Nevertheless, because of procurement morbidity and constraints on the quantity of autograft, surgeons also use allografts, xenografts, and synthetic materials. Many synthetic alternatives have been developed, but they are generally not as effective as natural materials due to the absence of osteoinductive and osteogenic properties. If synthetics were made more osteoinductive, they could provide an unlimited source of graft material that would eliminate many of the drawbacks of autograft, allograft, and xenograft. The goal of our Phase I application was to develop bi-functional peptide coatings that promote the attachment and retention of osteogenic growth factors and cells to tricalcium phosphate bone grafts. First, we identified tricalcium phosphate (TCP)-binding peptides using phage display techniques. Next, we synthesized combinations of the Affinergy novel Bone Morphogenetic Protein 2 (BMP-2), Platelet Derived Growth Factor-BB (PDGF-BB) and cell-binding sequences coupled to the newly identified TCP-binding peptides. These candidate bifunctional linker peptides were tested for their ability to bind BMP-2, PDGF-BB, and osteoblasts on TCP matrix, while retaining BMP-2 and PDGF-BB bioactivity and the osteoblastic phenotype. Here, we propose the extension of these studies by first optimizing our linker peptide sequences to generate the highest possible affinity binding peptides for TCP, BMP, PDGF and osteoblasts. We will also examine the commercializability of the peptide coating through an exhaustive battery of biocompatibility, sterilization and storage tests. A rabbit ulnar defect model will then be conducted to optimize dosage conditions and test the efficacy of new peptides. These data will provide key evidence for the in vivo efficacy and general commercializability of this bone graft coating system. Additional Phase III studies funded by Affinergy and/or new potential partnerships would likely involve a large animal model, and/or the identification and optimization of new peptide sequences in preparation for IDE submission. Public Health Significance: Bone grafting is routinely necessary prior to the placement of Dental implants. Natural materials like autograft (bone harvested from the patient) and allograft (cadaveric bone) have traditionally been used in these grafting procedures. Each strategy has unique limitations including complications associated with autograft harvest;and with allograft concerns regarding immunogenicity, risk of disease transmission, limited availability, and high procurement costs. Many synthetic alternatives have been developed, but they are generally not as effective as the natural materials. In this project, we are attempting to improve synthetic bone substitutes with the Affinergy linker peptides. We expect that peptide coatings will improve the ability of synthetic materials to stimulate bone healing by encouraging the attachment of bone promoting growth factors and cells on the surface of these synthetic alternatives.
| Hamilton, Paul T; Jansen, Michelle S; Ganesan, Sathya et al. (2013) Improved bone morphogenetic protein-2 retention in an injectable collagen matrix using bifunctional peptides. PLoS One 8:e70715 |
