The Molecular Mechanism of the Surface Charge of Piezoelectric Materials for Bone Regenerative Engineering

摘要 在美国，每年进行的骨骼重建手术超过100万例。电气 在临床上，刺激对骨的修复和再生有深远的影响。 申请。然而，目前的ES设备存在许多缺点，包括产生的效率低 电场(用于外部ES设备)、电刺激器中使用的体积大小和有毒材料，以及 植入的ES装置的不可降解性。可以产生电荷的压电材料 在变形过程中，反之亦然，可以用来制造自供电的电刺激器，它可以 有效刺激骨骼修复和再生。具体地说，压电体产生的电荷 表面的压电材料已被证明能有效地刺激干细胞的增殖、迁移 体外和体内的成骨分化和改建。然而，潜在的分子 负责这些观察的机制仍不清楚。初步结果表明， 生物材料表面的电荷可以改变钙信号通路，这可能具有内在的 刺激细胞基骨诱导蛋白生长因子的产生和分泌的成骨活性 (BMP-2)。这种资助申请的假设是，在压电材料上产生的表面电荷 会导致钙离子振荡和/或ECM蛋白吸附增强，这种变化可能触发茎 细胞成骨分化和/或基于细胞因子的诱导性自分泌和旁分泌环。这样做的主要目标是 应用于研究压电体表面电荷如何产生的基本分子机理 材料能积极影响愈合程度，促进骨组织再生。三个具体的 提出的目的是为了验证我们的建议的假设。在目标1中，我们将设计、制造和表征 用于研究成骨信号机制的压电材料。在目标2中，我们将研究钙离子如何 信号机制和/或ECM沉积响应于在 压电材料。在目标3中，使用微阵列，我们将检查各种基因的表达谱 压电支架上种植的间充质干细胞成骨分化相关基因的研究 材料。该项目的数据将提供必要的信息，以进一步探索 用于骨修复和再生应用的压电表面电荷。可实现的第一个里程碑 通过这项提议，开发了一种压电支架，并建立了研究成骨的装置 信号机制和支架本身的相关特性。第二个可以实现的里程碑 是评价钙信号转导机制的作用以及细胞外基质吸附对 在压电材料上产生的表面电荷。第三个里程碑是对 骨髓间充质干细胞在压电支架上成骨分化过程中多种基因的表达谱。

Abstract Each year in the United States, over 1 million bone reconstruction procedures are performed. Electrical stimulation (ES) has been shown to exhibit profound effects on bone repair and regeneration in clinical applications. However, current ES devices present many drawbacks including the inefficiency of generated electrical fields (for external ES devices), the bulky size and toxic materials used in electrical stimulators, and the non-degradability of implanted ES devices. Piezoelectric materials, which can generate electric charge during deformation and vice versa, can be employed to create self-powered electrical stimulators that can effectively to stimulate bone repair and regeneration. Specifically, piezoelectric charges generated on the surface of the piezoelectric materials have proven to effectively stimulate stem cell proliferation, migration, osteogenic differentiation and remodeling both in vitro and in vivo. However, the underlying molecular mechanism responsible for these observations is still unclear. The preliminary results demonstrated that surface charge on a biomaterial could alter the calcium signaling pathways, which could possess intrinsic osteoinductivity by stimulating the production and secretion of cell-based osteoinductive protein growth factor (BMP-2). The hypothesis of this grant application is that surface charge generated on piezoelectric materials will induce enhanced Ca2+ oscillation and/or ECM protein adsorption, and such a change may trigger the stem cell osteo-differentiation and/or cytokine-based inductive autocrine and paracrine loops. The main goal of this application is to investigate the fundamental molecular mechanism of how the surface charge of piezoelectric materials can positively influence the degree of healing and promote bone tissue regeneration. Three specific aims are proposed to test the hypothesis of our proposal. In Aim 1, we will design, fabricate, and characterize piezoelectric materials for the study of osteogenic signal mechanisms. In Aim 2, we will study how Ca2+ signaling mechanisms and/or ECM deposition in respond to the piezoelectric charges generated on the piezoelectric materials. In Aim 3, using microarrays, we will examine the expression profile of a variety of genes during osteogenic differentiation of the seeded mesenchymal stem cells (MSC) on the piezoelectric materials. The data from this project will provide the necessary information to explore further the nature of piezoelectric surface charge for bone repair and regeneration applications. The first milestone achievable through this proposal is the development of a piezoelectric scaffold and the setup for studying the osteogenic signaling mechanisms and the related characterizations of the scaffold itself. The second achievable milestone is the evaluation of the role of Ca2+ signaling mechanisms as well as ECM adsorption in response to the surface charges generated on the piezoelectric materials. The third milestone is the assessment of the expression profiles of a variety of genes during osteogenic differentiation of MSCs on the piezoelectric scaffold.