Bioactive Peptide Coatings for Synthetic Bone Grafts in Dental Applications

用于牙科应用中合成骨移植的生物活性肽涂层

• 批准号: 7535889
• 负责人: Hanne Gron
• 金额: $ 81.74万
• 依托单位: AFFINERGY ,INC
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7535889
• 关键词: Adult; Affinity; Age-Years; Allografting; Animal Model; Autologous Transplantation; Binding; Biocompatible Materials; Biological; Biological Assay; Biopolymers; Blood Platelets; Bone Substitutes; Bone Surface; Bone Transplantation; Cells; Chemistry; Clinical; Condition; Coupled; Data; Defect; Dental; Dental Implants; Development; Disease; Dose; Elements; Evaluation; Floor; Funding; Generations; Goals; Gold; Growth Factor; Harvest; Health; Human; Institutes; Laboratories; Ligation; Mediating; Metals; Modeling; Morbidity - disease rate; Numbers; Organ Transplantation; Oryctolagus cuniculus; Osteoblasts; Osteogenesis; Patients; Peptides; Periodontitis; Phage Display; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Phenotype; Placement; Plasma; Plastics; Platelet-Derived Growth Factor; Preparation; Procedures; Property; Proteins; Public Health; Quality of life; Range; Recombinant Proteins; Recombinants; Research; Resistance; Risk; Services; Sinus; Source; Specific qualifier value; Specificity; Standards of Weights and Measures; Stem cells; Sterilization for infection control; Surface; Surgeon; System; Techniques; Testing; Therapeutic; To specify; Tooth structure; Transplanted tissue; Xenograft procedure; base; biomaterial compatibility; bone; bone healing; bone loss; bone morphogenetic protein 2; commercialization; cost; craniofacial; design; disease transmission; dosage; immunogenicity; improved; in vivo; insight; interfacial; novel; osteoinductive factor; platelet-derived growth factor BB; protein aminoacid sequence; prototype; size; tricalcium phosphate

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.

描述（由申请人提供）：根据国家牙科和颅面研究研究所的说法，有86％的70岁以上的成年人至少患有适度的牙周炎，四分之一以上失去了牙齿，导致了严重的健康和生活质量的影响。由于牙周炎引起的骨质流失，在放置牙齿植入物之前，通常需要骨移植。自体移植骨被认为是黄金标准，因为其成骨细胞，骨诱导因子和骨导导特性。然而，由于采购发病率和自体量的限制，外科医生还使用同种异体移植，异种移植物和合成材料。已经开发了许多合成替代方法，但是由于缺乏骨倾向和成骨特性，它们通常不如天然材料有效。如果使合成剂变得更具骨诱导性，则可以提供无限的移植物材料来源，以消除自体移植，同种异体移植和异种移植的许多缺点。我们阶段应用的目的是开发双官能肽涂层，以促进成骨生长因子和细胞的附着和保留磷酸三中钙骨移植物。首先，我们使用噬菌体显示技术确定了磷酸三钙（TCP）结合肽。接下来，我们合成了新型骨形态发生蛋白2（BMP-2），血小板衍生的生长因子BB（PDGF-BB）和与新鉴定的TCP结合肽结合的细胞结合序列的组合。测试了这些候选双功能连接器肽在TCP基质上结合BMP-2，PDGF-BB和成骨细胞的能力，同时保留BMP-2和PDGF-BB生物活性和成骨分布性表型。在这里，我们通过首先优化我们的接头肽序列来扩展这些研究的扩展，以生成TCP，BMP，PDGF和成骨细胞的最高亲和结合肽。我们还将通过详尽的生物相容性，灭菌和储存测试来检查肽涂层的商业化性。然后将进行兔尺尺缺陷模型，以优化剂量条件并测试新肽的功效。这些数据将为该骨移植涂层系统的体内功效和一般商业化性提供关键证据。由Affinergy和/或新的潜在伙伴关系资助的其他第三阶段研究可能涉及大型动物模型，和/或对新肽​​序列的识别和优化，以准备IDE提交。公共卫生的意义：在放置牙科植入物之前，通常需要进行骨移植。自然材料（如自体移植（从患者那里收集）和同种异体移植物（尸体骨）传统上已用于这些嫁接程序。每种策略都有独特的局限性，包括与自体收成相关的并发症；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移植问题。已经开发了许多合成替代品，但通常不像天然材料那样有效。在这个项目中，我们试图用Affinergy接头肽改善合成骨替代物。我们预计，肽涂层将通过鼓励促进骨骼促进生长因子和细胞在这些合成替代方面的附着的附着来提高合成材料刺激骨骼愈合的能力。