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

描述(申请人提供)：创建支持细胞附着、生长和分化的仿生底物和支架是工程化组织发展的关键组成部分，这里提出的实验计划旨在为实现这一目标做出贡献。天然衍生材料(如胶原蛋白)已被广泛用作组织工程的支架材料，但存在明显的局限性(例如，有限的定制能力和对结构的控制)。使用促进细胞黏附的合成材料避免了许多与天然材料相关的限制，但这种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共聚物是一种很有前景的生物材料，因为这些聚合物具有模拟蛋白质的骨架(2-氨基酸残基)，并且可以快速组装成不同的功能形式；然而，尼龙-3聚合物在生物应用方面很少受到关注。PI最近公布了初步结果，表明尼龙-3共聚物在生物材料应用中具有吸引力(Lee等人，J.Am化学。SoC。131：16779(2009年))。具体地说，一些尼龙-3共聚物，当附着在表面时，被发现比阳性对照材料支持更大的细胞黏附和铺展。最好的尼龙-3共聚物在没有血清蛋白的情况下支持细胞附着和铺展。这里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共聚物的制备容易，利用该系统可以实现组成和结构变化的广度，将使我们能够识别具有优秀且可能独特的特征的样品作为组织工程工具。此外，这些化学特征应该能让我们更好地理解材料化学中离散的、可控的变化如何控制细胞的行为，从而产生可用于构建具有优化组成的支架的信息。尼龙-3体系特别适合于机械分析，因为可以通过传统的固相方法制备离散的低聚物或定义的低聚物混合物。我们的长期目标是创造新的尼龙-3材料，这种材料可以自发组装成三维网络(水凝胶)，对细胞具有物理和化学吸引力。这种材料可以为组织工程应用提供新型的支架。拟议的工作将集中于以下目标：1)阐明细胞与尼龙-3共聚物黏附的机制(S)，以及2)产生含有指导自组装的片段以及控制细胞黏附的片段的尼龙-3嵌段共聚物。 与公共健康相关：支持细胞黏附和生长的材料的产生在设计用于替代受损或患病组织的工程环境的建设中非常重要。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，但可以以仿生的方式表现。这些生物材料将使我们更好地了解细胞与周围环境相互作用和接收信息的方式，并将被用于创造一种新型的3D支架材料，用于再生医学应用。

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.