Functionalizing Hydroxyapatite With Proadhesive Peptides

描述（由申请人提供）：每年，数百万美国人接受某种类型的骨科或牙科植入物。关节假体（例如髋关节和膝关节）在恢复患者功能方面非常成功，但这些装置通常只能持续 10-15 年。用于填充骨缺损或病变的植入物更不发达；目前的治疗“黄金标准”是自体骨移植，但它具有许多相关的风险和局限性。最近，许多研究人员试图通过用模拟内源骨环境的分子（例如源自细胞外基质成分的肽）修饰生物材料来提高植入物性能。这种“仿生学方法”在增强某些类型材料的生物活性方面显示出很大的希望，然而，令人惊讶的是，骨传导性最强的一类材料——磷酸钙——在这方面受到的关注最少。为了解决生物材料研究中的这一缺陷，该项目的广泛、长期目标是确定模拟蛋白/肽，例如胶原蛋白衍生肽和骨形态发生蛋白-2 (BMP-2)，是否可以增强磷酸钙生物材料，特别是羟基磷灰石 (HA) 的骨整合。为了实现这一目标，我们设计了4个具体目标： 具体目标 1：鉴定可刺激最佳体外人间充质干细胞 (MSC) 附着和分化的仿生肽。 具体目标 2：确定具有额外结构域的工程肽是否增强肽束缚和/或生物活性。更具体地说，将通过添加HA结合序列或通过在HA和细胞结合基序之间插入多接头结构域来修饰肽。 具体目标 3：测试肽涂层在促进内源性 MSC 粘附和分化、从而增强骨形成方面的功效。大鼠胫骨植入模型将用于测试肽的体内功效。 具体目标 4：确定是否可以通过在支架上预装载 MSC 来改善骨整合。公共健康相关性：这项研究的主要目标是优化常用于关节假体和骨替代应用的磷酸钙生物材料的性能。

DESCRIPTION (provided by applicant): Every year, millions of Americans receive some type of orthopaedic or dental implant. Joint prostheses (e.g. hip and knee) have been very successful in restoring function to patients, however these devices generally last only 10-15 years. Implants used for filling bone defects or lesions are even less well-developed; the current "gold standard" for treatment is autologous bone graft, which carries many associated risks and limitations. Recently, many investigators have sought to improve implant performance by modifying biomaterials with molecules that mimic the endogenous bone environment, for example, peptides derived from components of the extracellular matrix. This "biomimetics approach" has shown much promise for enhancing the bioactivity of certain types of materials, however, surprisingly, the class of materials that is among the most osseoconductive, the calcium phosphates, has received the least amount of attention in this regard. To address this deficit in biomaterials research, the broad, long-term goal of this project is to determine whether mimetic proteins/peptides, such as collagen l-derived peptides and Bone Morphogenic Protein-2 (BMP-2), can enhance the osseointegration of calcium phosphate biomaterials, particularly hydroxyapatite (HA). To accomplish this goal, we have designed 4 specific aims: Specific Aim 1: To identify biomimetic peptides that stimulate optimal in vitro human mesenchymal stem cell (MSC) attachment and differentiation. Specific Aim 2: To determine whether engineering peptides with additional domains enhances peptide tethering and/or bioactivity. More specifically, peptides will be modified by adding an HA-binding sequence, or by inserting a polylinker domain between the HA- and cell-binding motifs. Specific Aim 3: To test the efficacy of peptide coatings in promoting adhesion and differentiation of endogenous MSCs, leading to enhanced bone formation. A rat tibial implantation model will be used to test peptide efficacy in vivo. Specific Aim 4: To determine whether osseointegration can be improved by pre-loading scaffolds with MSCs. Public-health relatedness: The major goal of this study is to optimize the performance of calcium phosphate biomaterials that are commonly used for joint prosthetic and bone replacement applications.