Nylon-3 Copolymers as Synthetic Cell-Adhesive Moieties for Tissue Engineering

描述（由申请人提供）：创建支持细胞附着、生长和分化的仿生基质和支架是工程组织开发的关键组成部分，本文提出的实验计划旨在促进实现这一目标。天然来源的材料（例如，胶原蛋白）已被广泛探索作为组织工程的支架，但伴随着显著的局限性（例如，有限的定制能力和对体系结构的控制）。促进细胞粘附的合成材料的使用避免了与天然材料相关的许多限制，但此类材料通常需要劳动密集型的合成方案，这阻碍了它们作为组织工程支架的广泛使用。尼龙-3共聚物作为有前景的生物材料是令人感兴趣的，因为这些聚合物具有蛋白质模拟骨架（2-氨基酸残基），并且可以以功能多样的形式快速组装;然而，尼龙-3聚合物在生物应用方面很少受到关注。PI最近提出了初步结果，表明尼龙-3共聚物对于生物材料应用是有吸引力的（Lee等人，J. Am. 131：16779（2009））。具体来说，发现一些尼龙-3共聚物在附着到表面时比阳性对照材料支持更大的细胞粘附和扩散。最好的尼龙-3共聚物支持细胞的附着和扩展在血清蛋白的情况下。本文提出的研究建立在这些初步发现的基础上。我们的一般假设是，尼龙-3共聚物可以容易地制备和宽度的组成和架构的变化，可以实现与此系统将使我们能够识别具有优异的和可能独特的特性作为工具的组织工程的例子。此外，这些化学特征应该使我们能够更好地了解材料化学中离散的、受控的变化如何控制细胞行为，从而产生可用于构建具有优化组成的支架的信息。尼龙-3体系特别适合于机理分析，因为离散的低聚物或限定的低聚物混合物可以通过常规的固相方法制备。我们的长期目标是创造新的尼龙-3材料，这些材料可以自发地组装成三维网络（水凝胶），这些网络在物理和化学上对细胞有吸引力。这些材料可以为组织工程应用提供新型支架。拟开展的工作将侧重于以下目标：1）阐明细胞粘附于尼龙-3共聚物的机制，以及2）生成含有指导自组装的链段以及控制细胞粘附的链段的尼龙-3嵌段共聚物。 公共卫生相关性：支持细胞粘附和生长的材料的产生在设计用于替换受损或患病组织的工程化环境的构建中是重要的。在这项提案中，我们的目标是创造和表征新型生物材料，这些材料在结构上是合成的，但可以以仿生方式表现。这些生物材料将使我们能够更好地了解细胞与周围环境相互作用并从周围环境接收信息的方式，并将用于创建用于再生医学应用的新型3D支架材料。

DESCRIPTION (provided by applicant): The creation of biomimetic substrates and scaffolds that support cell attachment, growth, and differentiation is a crucial component in the development of engineered tissues, and the experimental program proposed here aims to contribute to the achievement of this goal. Naturally-derived materials (e.g., collagen) have been widely explored as scaffolds for tissue engineering, but are accompanied by significant limitations (e.g., limited tailor ability and control over architecture). The use of synthetic materials that encourage cell adhesion avoids many of the limitations associated with natural materials, but such materials often require labor-intensive synthetic protocols, which hinders their widespread use as tissue engineering scaffolds. Nylon-3 copolymers are intriguing as prospective biomaterials because these polymers have a protein-mimetic backbone (2-amino acid residues) and can be assembled rapidly in functionally diverse forms; however, nylon-3 polymers have received very little attention in terms of biological applications. The PIs have recently presented preliminary results showing that nylon-3 copolymers are attractive for biomaterials applications (Lee et al., J. Am. Chem. Soc. 131:16779 (2009)). Specifically, some nylon-3 copolymers, when attached to a surface, were found to support greater cell adhesion and spreading than did positive control materials. The best of the nylon-3 copolymers supported cell attachment and spreading in the absence of serum proteins. The research proposed here builds on these initial discoveries. Our general hypothesis is that the ease with which nylon-3 copolymers can be prepared and the breadth of compositional and architectural variation that can be achieved with this system will enable us to identify examples with excellent and possibly unique characteristics as tools for tissue engineering. Moreover, these chemical features should allow us to gain a better understanding of how discrete, controlled changes in materials chemistry can control cell behavior, thereby yielding information that can be used to construct scaffolds with an optimized composition. The nylon-3 system is particularly amenable to mechanistic analysis because discrete oligomers or defined oligomer mixtures can be prepared via conventional solid-phase methods. Our long-range goal is to create new nylon-3 materials that spontaneously assemble into three- dimensional networks (hydrogels) that are physically and chemically attractive to cells. Such materials could provide new types of scaffolds for tissue engineering applications. The proposed work will focus upon the aims of: 1) Elucidating the mechanism(s) by which cells adhere to nylon-3 copolymers, and 2) Generating nylon-3 block copolymers containing segments that direct self-assembly as well as segments that control cell adhesion. PUBLIC HEALTH RELEVANCE: The generation of materials that support cell adhesion and growth is important in the construction of engineered environments that are designed to replace damaged or diseased tissues. In this proposal, we aim to create and characterize new types of biomaterials that are synthetic in structure, but that can behave in a biomimetic manner. These biomaterials will allow us to better understand the manner in which cells interact with and receive information from their surroundings, and will be used to create a new type of 3-D scaffold material for use in regenerative medicine applications.