Multifunctional Tropoelastin-Silk Biomaterial Systems

描述(由申请人提供)：需要新的多功能、可降解、聚合物生物材料系统，该系统可以在体外和体内为特定的细胞和组织需求量身定做。虽然蛋白质-蛋白质复合体主导着我们体内的组织结构和功能，但我们一直无法概括这种系统在体外对新生物材料的复杂性和控制性，以便指导细胞和组织功能。例如，能够形成机械坚固和耐用的生物材料以提供高度灵活和动态的生物材料的材料系统仍然是一个挑战。我们的目标是构建一组能够覆盖一系列物理特性的复合蛋白质生物材料，以模拟不同组织结构的弹性和相应的控制生物功能的能力--例如直接干细胞反应。假设是高度弹性和动态的结构蛋白(原弹性蛋白)与坚韧、耐用的蛋白质(丝素)相结合，将产生新的多功能蛋白质复合系统，可以为生物材料领域提供广泛的实用平台。我们建议基于这两种成熟的结构蛋白，原弹性蛋白和丝素的组合，生成一种新的高度可控的复合纤维蛋白系统，这两种蛋白聚合物都是生物可降解的，具有良好的生物相容性。这些蛋白质涵盖了一系列生物材料需求；原弹性蛋白提供了高度灵活和动态的结构特征，丝素提供了机械韧性和缓慢的降解。我们对这两种结构蛋白之间分子尺度相互作用的发现，构成了本提案的基础。实验计划主要集中在：(A)进一步阐明原弹性蛋白和丝素之间的机制相互作用，以优化材料结构和功能的控制；(B)利用hMSCs和皮质神经元，评估产生的一系列材料的细胞相互作用，以了解蛋白质成分、材料顺应性和细胞结果之间的关系，并在体内筛选材料降解情况和炎症反应，以及(C)开发利用这些系统可实现的动态材料特性，以支持体外细胞功能。实验计划得到了大量初步数据的支持，这些数据表明我们有能力产生所需的材料(原弹性蛋白、丝素)，使材料功能化(例如，表面化学)，以机械的洞察力探索两种成分之间的相互作用，将蛋白质加工成新的材料形式，并根据组成直接在这些材料上产生细胞结果。这些计划的总体结果将是一个新的蛋白质复合生物材料平台，它将满足生物材料领域的一个重要需求，与坚固但灵活的系统和强大、耐用的系统直接相关。

DESCRIPTION (provided by applicant): New multifunctional, degradable, polymeric biomaterial systems are needed that can be tailored to specific cell and tissue needs in vitro and in vivo. While protein-protein composites dominate tissue structure and function in our bodies, we have been unable to recapitulate the complexity and control of such systems in vitro for new biomaterials in order to direct cell and tissue functions. For example, material systems that can form mechanically robust and durable biomaterials to give highly flexible and dynamic biomaterials, remains a challenge. Our goal is to construct a panel of composite protein biomaterials that can cover a range of physical properties, to mimic the elasticity of diverse tissue structures and the consequential ability to control biological function - such as to direct stem cell responses. The hypothesis is that combinations of a highly elastic and dynamic structural protein (tropoelastin) with tough, durable proteins (silk) will generate new multifunctional protein composite systems that can offer a broad platform of utility to the biomaterials field. We propose to generate a new family of highly controllable composite fibrous protein systems, based on combinations of these two well-established structural proteins, tropoelastin and silk, both biodegradable protein polymers with good biocompatibility. These proteins encompass a range of biomaterial needs; tropoelastin provides highly flexible and dynamic structural features, silk provides mechanical toughness and slow degradation. Our findings of molecular-scale interactions between these two structural proteins, forms the basis of the present proposal. The experimental plans are focused on: (a) further elucidation of the mechanistic interactions between tropoelastin and silk to optimize control of material structure and function, (b) assessment of cell interactions for the range of materials generated to understand relationships between the protein composites, material compliance and cell outcomes, using hMSCs and cortical neurons, and in vivo screens of material degradation profiles and inflammatory responses, and (c) exploitation of the dynamic material properties achievable with these systems towards support of cell functions in vitro. The experimental plans are supported by extensive preliminary data that demonstrate our ability to generate the required materials (tropoelastin, silks), to functionalize the materials (e.g., surface chemistry),to probe the interactions among the two components with mechanistic insight, to process the proteins into new material formats, and to direct cell outcomes on these materials with outcomes dependent on the composition. The overall outcome from the plans would be a new protein composite biomaterials platform that would fill an important need in the field of biomaterials, with direct relevance to tough but flexible systems and strong, durable systems.