Nanoscale engineering of erodible drug delivery matrices

描述（由申请人提供）：现代生物材料研究的范式是设计能够对特定刺激做出反应并引发所需生物反应的材料。结构生物学对生物大分子和细胞行为的定量理解的革命为合理设计具有理想生物活性的材料提供了重要信息。该提案的主要目标之一是通过生物学上重要的蛋白质（如生长因子）和多糖之间的相互作用组装新型非共价交联的水凝胶基质;将操纵缔合的热力学和动力学以控制材料性质和释放曲线。用于控制组装的相互作用也将允许通过与细胞表面受体的配体交换来递送蛋白质。利用配体交换机制作为递送和侵蚀的策略将与其中细胞过表达某些受体的许多体内过程相关，并且通过这种独特的活性协调，基质将应用于生长因子的靶向递送，用于化学治疗、组织工程和伤口愈合应用。 除了生产用于大分子递送的新型材料外，这项工作还将利用新的定量方法来表征这些生物材料在与细胞相关的长度和时间尺度上的机械反应。新的定量方法，如示踪粒子微观流变学和显微操作与激光镊子将被应用于直接测量这些水凝胶的微观力学和弛豫时间尺度。当与上述合成策略相结合时，这些研究将使我们能够理解非共价分子相互作用对水凝胶基质的结构和流变学性质的具体影响。这将允许合理设计微观机械响应、分子递送动力学和细胞过程的长度和时间尺度上的功能。因此，所提出的策略将导致细胞和聚合物反应耦合的材料，并将广泛影响针对特定细胞事件的新生物材料的开发。

DESCRIPTION (provided by applicant): The paradigm of modern biomaterials research is the design of materials that can respond to specific stimuli and elicit a desired biological response. The revolution in structural biology toward quantitative understanding of biomacromolecular and cellular behavior offers important information for the rational design of materials with desirable bioactivity. One of the primary goals of this proposal is the assembly of novel, noncovalently crosslinked hydrogel matrices via the interaction between biologically important proteins (such as growth factors) and polysaccharides; the thermodynamics and kinetics of the association will be manipulated to control materials properties and release profiles. The interactions used to control assembly will also permit delivery of the proteins by ligand exchange with cell surface receptors. Exploiting ligand exchange mechanisms as a strategy for delivery and erosion will be relevant to many in vivo processes in which cells overexpress certain receptors, and by this unique coordination of activities, the matrices will find application in the targeted delivery of growth factors for chemotherapeutic, tissue engineering, and wound healing applications. In addition to producing novel materials for macromolecular delivery, this work will also utilize new quantitative approaches for characterizing the mechanical response of these biomaterials on length and timescales that are relevant to cells. New quantitative approaches such as tracer particle microrheology and micromanipulation with laser tweezers will be applied to directly measure microscopic mechanics and relaxation timescales of these hydrogels. When coupled with the synthetic strategies above, these investigations will allow us to understand the specific impact of noncovalent molecular interactions on the structure and rheological properties of hydrogel matrices. This will permit the rational design of microscopic mechanical responses, molecular delivery kinetics, and functionality on length and timescales of cellular processes. The proposed strategies will therefore result in materials in which cellular and polymer responses are coupled, and will broadly impact the development of new biomaterials targeted to specific cellular events.