Improved Orthopedic Implant Surface Coatings

描述（由申请人提供）：许多当代医学和牙科疗法包括使用金属等材料替代或修复组织。目前，美国每年至少进行15万例髋关节置换术、30万例膝关节置换术和50万例植牙手术（Kurtz, Mowat et al. 2005）。随着婴儿潮一代的年龄增长，这些数字预计还会增加。虽然很多人都经历了简单的愈合，但与金属种植体相关的并发症也很多。例如，关节置换术的翻修率在10-20%之间（Fitzpatrick, Shortall et al. 1998），据估计，美国每年的关节手术总数中有16%是翻修（mahmoud, Barrett et al. 2003）。这些修改大多是由于在种植体-骨界面失败，这表明需要改进技术来增加种植体上的骨生长。提高金属植入体的集成度将有利于社会受益于下一代设备。在第一阶段，我们使用噬菌体展示来鉴定与钛高亲和力结合的肽。这些钛结合肽与细胞附着RGD序列相结合，生成促进成骨细胞在钛上快速附着和分化的肽。我们还鉴定了独特的一般细胞附着序列和对骨形态发生蛋白2具有高亲和力的肽段。第二阶段的目标是开发一种用于金属种植体的IFBM涂层原型，以促进细胞附着并改善骨整合。在第二阶段，我们将把这些进展结合起来开发一种涂层，该涂层利用：1)改良的金属，2)改良的细胞，3)BMP结合肽来促进金属植入物的骨整合。在目标1中，我们将：1)优化生物液体存在下的金属结合肽；2)鉴定与成骨细胞特异性结合的肽。在目标2中，我们将生成不同类别的IFBMs: 1)促进成骨细胞祖细胞附着的一般细胞结合肽；2)促进成熟成骨细胞附着的成骨细胞特异性结合肽；3)一种BMP-2结合肽，招募、结合并保留BMP-2和BMP家族的其他成员。每一类IFBM将分别在一系列体外分析中进行测试。然后将ifbm结合在一起，生成一种混合涂层，该涂层将结合并引导钛表面的成骨细胞和BMP-2的生物反应。在目标3中，我们将完成：1)生物物理，2)分子，3)机械和4)原型ifbm的毒理学表征。最后，在目标4中，我们将与D. Rick Sumner博士（Kuroda, Virdi et al. 2004）合作，在大鼠股骨骨整合模型中检验这些IFBM涂层的功效。在成功完成第二阶段后，第三阶段将涉及在大型动物模型中测试原型涂层，例如犬肱骨模型的间隙愈合（Sumner, Turner et al. 2004）或犬髋关节置换模型（Sumner, Turner et al. 2001）。

DESCRIPTION (provided by applicant): Many contemporary medical and dental therapies include the replacement or repair of tissues using materials such as metal. Currently there are at least 150,000 hip replacements, 300,000 knee replacements, and 500,000 dental implant procedures performed in the US each year (Kurtz, Mowat et al. 2005). These numbers are expected to increase as the baby boom generation ages. While a large number of individuals experience uncomplicated healing, there are a significant number of complications associated with metal implants. For example, the revision rate for arthroplasty varies between 10-20% (Fitzpatrick, Shortall et al. 1998) and it has been estimated that 16% of the annual total joint surgeries in the US are revisions (Mahomed, Barrett et al. 2003). The majority of these revisions are due to failure at the implant-bone interface, suggesting a need for improved technologies to increase bone growth onto the implants. Improving the integration of metal implants will be advantageous to society benefiting from next generation devices. In phase I, we used phage display to identify peptides that bound to titanium with high affinity. These titanium-binding peptides were synthetically linked to a cell attachment RGD sequence to generate peptides that promoted rapid attachment and differentiation of osteogenic cells on titanium. We have also identified unique general cell attachment sequences and peptides with high affinity for Bone Morphogenetic Protein 2. The goal of this Phase II proposal will be to develop a prototype IFBM coating for metal implants that promotes cell attachment and improves osseointegration. In Phase II, we will bring these advances together to develop a coating that utilizes: 1) improved metal, 2) improved cell, and 3) BMP binding peptides to promote osseointegration of metal implants. In aim 1 we will: 1) optimize metal-binding peptides in the presence of biologic fluids and 2) identify peptides that bind specifically to osteoblasts. In aim 2, we will generate different classes of IFBMs: 1) a general cell-binding peptide that promotes the attachment of osteoblast-progenitors; 2) an osteoblast specific binding peptide that promotes mature osteoblast attachment; 3) a BMP-2 binding peptide that recruits, binds, and retains BMP-2 and other members of the BMP family. Each class of IFBM will be tested individually in a series of in vitro assays. IFBMs will then be combined to generate a mixed coating that will bind and guide the biologic response of osteogenic cells and BMP-2 on the surface of titanium. In aim 3, we will complete: 1) biophysical, 2) molecular, 3) mechanical, and 4) toxicological characterization of prototype IFBMs. Finally in aim 4, we will examine the efficacy of these IFBM coatings in a rat femoral model of osseointegration in collaboration with Dr. D. Rick Sumner (Kuroda, Virdi et al. 2004). Upon successful completion of Phase II, Phase III would involve testing the prototype coating in a large animal model such as gap healing in a canine humeral model (Sumner, Turner et al. 2004) or a canine hip replacement model (Sumner, Turner et al. 2001).