Bioactive Peptide Coatings for Synthetic Bone Grafts in Dental Applications

描述（由申请人提供）：根据国家牙科和颅面研究所的数据，70岁以上的成年人中有86%至少患有中度牙周炎，超过四分之一的人已经失去了牙齿，这对健康和生活质量造成了严重的影响。由于这种疾病会导致骨质流失，在植牙之前通常需要植骨。自体骨移植被认为是金标准，因为它具有成骨细胞、骨诱导因子和骨导电性。然而，由于自体移植物的获取困难和数量限制，外科医生也使用同种异体移植物、异种移植物和合成材料。同种异体移植物和异种移植物是受欢迎的，因为它们具有一些骨诱导因子，特别是在脱矿形式。然而，这些天然材料也有局限性，包括免疫原性、疾病传播风险、供应有限和采购成本高。许多人工合成的替代品已经开发出来，但由于缺乏成骨和成骨的特性，它们通常不如天然材料有效。在这个项目中，我们正在尝试用affinenergy的连接肽来改进人工骨替代品。如果合成材料具有更强的骨诱导性，它们将提供无限的移植物材料来源，从而消除自体移植物、同种异体移植物和异种移植物的许多缺点。Affinergy的肽连接物对现有的骨移植提供了两个改进，可以通过刺激骨愈合显着改善临床结果。首先，我们期望用结合肽包覆骨移植材料将显著提高其保留外源递送的成骨因子（如重组蛋白和祖细胞）的能力。其次，我们相信这些肽涂层具有促进内源性生长因子和细胞附着在骨移植物表面的潜力。本研究的目的是证明双功能肽涂层可以通过增加成骨生长因子和细胞的附着和保留来提高人工骨移植物促进骨愈合的能力。首先，利用噬菌体展示技术，我们将鉴定磷酸三钙（TCP）结合肽。接下来，我们将合成affinenergy现有的BMP-2和成骨细胞结合序列与新鉴定的TCP结合肽的组合。这些候选的双功能连接肽将被测试其在TCP基质上结合BMP-2和成骨细胞的能力，同时保持BMP-2的活性和成骨细胞的表型。最后，将使用大鼠下颌骨缺损模型来研究肽包被在低剂量重组BMP-2下促进骨形成的能力。生长因子和成骨细胞结合肽也将被单独和联合测试，以评估它们通过促进内源性生长因子和骨祖细胞的附着，与未经治疗的TCP相比，增加骨形成的能力。植骨在植牙前通常是必要的。天然材料，如自体移植物，从病人身上采集的骨，同种异体移植物，尸体骨，传统上用于这些移植手术。它们有许多局限性，包括自体移植物摘取的并发症；与同种异体移植物相关的免疫原性、疾病传播风险、有限的可用性和高采购成本。已经开发了许多合成替代品，但它们通常不如天然材料有效。在这个项目中，我们正在尝试用affinenergy的连接肽来改进人工骨替代品。我们期望肽涂层将通过促进骨促生长因子和细胞在这些合成替代品表面的附着来提高合成材料刺激骨愈合的能力。

DESCRIPTION (provided by applicant): According to the National Institute of Dental and Craniofacial Research, 86% of adults over 70 years have at least moderate periodontitis and over a quarter have lost their teeth, which has serious repercussion on health and quality of life. Because of bone loss caused by this disease, bone grafting is routinely necessary prior to the placement of dental implants. Autograft bone is considered the gold standard because of its osteogenic cells, osteoinductive factors, and osteoconductive properties. However, because of procurement morbidity and constraints on the quantity of autograft, surgeons also use allografts, xenografts, and synthetic materials. Allograft and xenograft are favored because they possess some osteoinductive elements especially in demineralized forms. However, these natural materials also have limitations including 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 due to the absence of osteoinductive and osteogenic properties. In this project, we are attempting to improve synthetic bone substitutes with Affinergy's linker peptides. 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. Affinergy's peptide linkers provide two improvements on existing bone grafts that could significantly improve clinical outcomes by stimulating bone healing. First, we expect that coating bone graft materials with binding peptides will significantly improve their ability to retain exogenously delivered osteogenic factors such as recombinant proteins and progenitor cells. Secondly, we believe these peptide coatings have the potential to promote the attachment of endogenous growth factors and cells onto the surface of bone grafts. The goal of this proposal is to demonstrate that bi-functional peptide coatings can improve the ability of a synthetic bone graft to promote bone healing by increasing the attachment and retention of osteogenic growth factors and cells. First, using phage display techniques, we will identify tricalcium phosphate (TCP) binding peptides. Next, we will synthesize combinations of Affinergy's existing BMP-2 and osteoblast binding sequences and the newly identified TCP binding peptides. These candidate bi-functional linker peptides will be tested for their ability to bind BMP-2 and osteoblasts on TCP matix, while retaining BMP-2's activity and the osteolbasts' phenotype. Finally, a rat mandible defect model will be used to investigate the ability of peptide coatings to increase bone formation at lower doses of recombinant BMP-2. Growth factor and osteoblast binding peptides will also be tested alone and in combination to assess their ability to increase bone formation compared to untreated TCP by promoting the attachment of endogenous growth factors and osteoprogenitor cells. Bone grafting is routinely necessary prior to the placement of dental implants. Natural materials like autograft, bone harvest from the patient, and allograft, cadaveric bone, have traditionally been used in these grafting procedures. They have many limitations including complications associated with autograft harvest; and immunogenicity, risk of disease transmission, limited availability, and high procurement costs associated with allograft. 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 Affinergy's linker peptides. We expect that peptide coatings will improve the ability of synthetic materials to stimulate bone healing by promoting the attachment of bone promoting growth factors and cells on the surface of these synthetic alternatives.