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，超过四分之一的人失去了牙齿，导致严重的健康和生活质量影响。由于牙周炎引起的骨质流失，在植入牙种植体之前，骨移植是常规必要的。自体骨被认为是金标准，因为它的成骨细胞，骨诱导因子和骨传导特性。然而，由于采购发病率和限制的自体移植物的数量，外科医生也使用同种异体移植物，异种移植物和合成材料。已经开发了许多合成替代品，但由于缺乏骨诱导和成骨特性，它们通常不如天然材料有效。如果合成材料具有更强的骨诱导性，它们可以提供无限的移植材料来源，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。我们第一阶段申请的目标是开发双功能肽涂层，促进成骨生长因子和细胞附着和保留磷酸三钙骨移植物。首先，我们使用噬菌体展示技术鉴定磷酸三钙（TCP）结合肽。接下来，我们合成了Affinergy新型骨形态发生蛋白2（BMP-2），血小板衍生生长因子-BB（PDGF-BB）和细胞结合序列与新鉴定的TCP结合肽的组合。测试这些候选双功能接头肽结合TCP基质上的BMP-2、PDGF-BB和成骨细胞的能力，同时保留BMP-2和PDGF-BB生物活性和成骨细胞表型。在这里，我们提出了这些研究的扩展，首先优化我们的接头肽序列，以产生TCP，BMP，PDGF和成骨细胞的最高可能的亲和力结合肽。我们还将通过一系列详尽的生物相容性、灭菌和储存测试来检查肽涂层的商业化能力。然后将进行兔尺骨缺损模型以优化剂量条件并测试新肽的功效。这些数据将为该植骨涂层系统的体内有效性和一般商业化提供关键证据。由Affinergy和/或新的潜在合作伙伴资助的其他III期研究可能涉及大型动物模型，和/或鉴定和优化新的肽序列，为IDE提交做准备。公共卫生意义：骨移植是常规必要的牙齿植入物放置之前。天然材料，如自体移植物（从患者身上采集的骨）和同种异体移植物（尸体骨）传统上用于这些移植手术。每种策略都有其独特的局限性，包括与自体移植物收获相关的并发症;以及关于免疫原性、疾病传播风险、有限的可用性和高采购成本的同种异体移植物问题。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，我们试图用Affinergy接头肽改进合成骨替代物。我们预计肽涂层将通过促进骨促进生长因子和细胞附着在这些合成替代品的表面上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 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.