Functionalizing Hydroxyapatite With Proadhesive Peptides

描述(申请人提供)：每年，数以百万计的美国人接受某种类型的矫形或牙科植入。关节假体(如髋关节和膝关节)在恢复患者功能方面非常成功，但这些设备通常只使用10-15年。用于填充骨缺损或病变的植入物甚至更不发达；目前治疗的“黄金标准”是自体骨移植，这带来了许多相关的风险和限制。最近，许多研究人员试图通过使用模拟内源性骨环境的分子来修饰生物材料来改善植入性能，例如，从细胞外基质成分中提取的多肽。这种“仿生学方法”在提高某些类型材料的生物活性方面大有可为，然而，令人惊讶的是，在这方面，骨传导最强的材料之一--磷酸钙--却受到的关注最少。为了解决生物材料研究中的这一不足，该项目的长期目标是确定模拟蛋白/多肽，如胶原L衍生的多肽和骨形态发生蛋白-2，是否能够促进磷酸钙生物材料，特别是羟基磷灰石(HA)的骨整合。为实现这一目标，我们设计了4个具体目标： 具体目的1：寻找在体外刺激人骨髓间充质干细胞(MSC)贴壁和分化的仿生肽。 具体目标2：确定带有额外结构域的工程多肽是否增强了多肽的锚链和/或生物活性。更具体地说，多肽将通过添加HA结合序列或通过在HA结合基序和细胞结合基序之间插入多连接器域进行修饰。 具体目的3：测试多肽涂层促进内源性MSCs黏附和分化的效果，从而促进骨形成。将使用大鼠胫骨植入模型在体内测试多肽的效果。 具体目的4：确定预加载间充质干细胞的支架能否改善骨结合。与公共健康相关：这项研究的主要目标是优化通常用于关节假体和骨置换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.