Highly Tunable Brush-Like Polymer Architectures to Control Therapeutic Delivery and Cell-Material Interactions

高度可调的刷状聚合物架构，用于控制治疗传递和细胞材料相互作用

• 批准号: 10669252
• 负责人: Kelly Anne Burke
• 金额: $ 37.62万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669252
• 关键词: Affect; Anesthetics; Architecture; Biocompatible Materials; Biology; Brush Cell; Bupivacaine; Cardiotoxicity; Cell Communication; Cells; Collection; Connective Tissue; Data; Diffusion; Encapsulated; Exposure to; Fibroins; Film; Formulation; Frustration; Goals; Growth; Immune; Immune response; Implant; In Vitro; Injectable; Knowledge; Laboratory Research; Length; Liquid substance; Local Anesthetics; Methods; Modeling; Modification; Morphology; Muscle; Nerve Block; Operative Surgical Procedures; Phagocytosis; Pharmaceutical Preparations; Phase; Poaceae; Polymers; Postoperative Pain; Property; Proteins; Public Health; Research Project Grants; Science; Shapes; Silk; Site; Statistical Data Interpretation; Structure; Surface; Testing; Therapeutic; Tissues; Variant; Work; biomaterial interface; cell type; design; immunoengineering; implant material; in vivo; in vivo Model; local drug delivery; molecular assembly/self assembly; molecular scale; mouse model; nanoscale; particle; pharmacokinetic model; prescription opioid; programs; rational design; response; success; surgical pain; tissue culture; tool; viscoelasticity; Affect; Anesthetics; Architecture; Biocompatible Materials; Biology; Brush Cell; Bupivacaine; Cardiotoxicity; Cell Communication; Cells; Collection; Connective Tissue; Data; Diffusion; Encapsulated; Exposure to; Fibroins; Film; Formulation; Frustration; Goals; Growth; Immune; Immune response; Implant; In Vitro; Injectable; Knowledge; Laboratory Research; Length; Liquid substance; Local Anesthetics; Methods; Modeling; Modification; Morphology; Muscle; Nerve Block; Operative Surgical Procedures; Phagocytosis; Pharmaceutical Preparations; Phase; Poaceae; Polymers; Postoperative Pain; Property; Proteins; Public Health; Research Project Grants; Science; Shapes; Silk; Site; Statistical Data Interpretation; Structure; Surface; Testing; Therapeutic; Tissues; Variant; Work; biomaterial interface; cell type; design; immunoengineering; implant material; in vivo; in vivo Model; local drug delivery; molecular assembly/self assembly; molecular scale; mouse model; nanoscale; particle; pharmacokinetic model; prescription opioid; programs; rational design; response; success; surgical pain; tissue culture; tool; viscoelasticity

My laboratory’s research projects combine my expertise in polymer science and biology to develop precise synthetic tools for problems at biomaterial interfaces. We approach these problems by designing materials from the “bottom up,” which is the idea that macroscale properties arise from the collection of interactions that occur at the molecular scale, nanoscale, and microscale. Our projects seek to program precise macroscale properties by controlling molecular assembly, and we then use the new substrates to ask questions about muscle, immune, and connective tissue biology using in vitro tissue culture and in vivo models. As an example, our ongoing work advances this goal by synthesizing cytocompatible liquid crystalline substrates to ask questions about how variations in viscoelasticity at subcellular, cellular, and supercellular length scales impact cellular responses. This MIRA program is motivated by the idea that brush-like polymer surfaces have significant and untapped potential as biomaterials. The concept features the spatially-controlled growth of polymers from natural biomaterial surfaces using synthetic methods to control the composition, connectivity, and morphology of the polymers. At a minimum, the projects will establish a new synthetic platform for brush-like polymers on silk fibroin substrates (films and particles) and will use the platform to generate new knowledge of brush-brush and brush- cell associations to tune interactions with implanted materials. In addition, the projects are unified in their goals to develop the brush-like polymer architecture for local drug delivery with specific focus on the anesthetic bupivacaine. Bupivacaine solutions are often applied directly at a surgical site to treat post-operative pain. While many bupivacaine formulations have been tested, nearly all rely on the diffusion of free drug or drug encapsulated in a polymer. No formulation achieves the sustained release required for postoperative pain, and repeat bupivacaine administration is prohibited due to cardiac toxicity, creating a critical treatment gap. These projects build upon our recent successes generating high degrees of functionalization on purified silk fibroin, a protein whose composition and secondary structure often frustrate modification efforts. Over the next five years, we will synthesize brush-like polymers of varying composition to quantify how the brush morphology and connectivity with neighbors affect the loading and release of varying drugs. Using release data to generate pharmacokinetic models and statistical analysis, we will rationally design multi-composition brushes for the phased release of local anesthetic to establish the brushes’ delivery efficacy and impact on tissues in an in vivo mouse model of surgical pain. Finally, injectable brush formulations will be generated on particles of varying shapes and sizes to establish how the polymer architecture impacts phagocytosis, targeting of specific cell types, and efficacy in a nerve block model. Ultimately, we will build upon our efforts to discover new, well-controlled polymer designs that alter protein interactions and cellular responses to feed into our lab’s broader goals to use materials to engineer immune responses and enhance integration with surrounding tissues.

我实验室的研究项目结合了我在聚合物科学和生物学方面的专业知识，以发展精度 生物材料界面问题的合成工具。我们通过设计材料来解决这些问题 “自下而上”，这是宏观属性源于发生的交互的想法 在分子量表，纳米级和微观上。我们的项目寻求编程精确的宏观属性 通过控制分子组件，然后我们使用新的底物提出有关肌肉，免疫，， 并使用体外组织培养和体内模型连接组织生物学。例如，我们正在进行的工作 通过合成细胞相容液晶底物来提出这一目标，以询问有关如何 亚细胞，细胞和超细胞长度尺度上粘弹性的变化会影响细胞反应。 这个MIRA程序是由类似刷子的聚合物表面具有重大且未开发的想法的动机 潜力作为生物材料。该概念以天然的聚合物的空间控制生长为特征 使用合成方法来控制生物材料表面 聚合物。这些项目至少将建立一个新的合成平台，用于在丝正素上类似刷子的聚合物 底物（膜和颗粒），将使用该平台来产生刷刷和刷子的新知识 与植入材料相互作用的细胞关联。此外，项目的目标是统一的 开发类似刷子的聚合物架构，用于局部药物输送，特别关注麻醉 布比卡因。布比卡因溶液通常直接在手术部位应用，以治疗术后疼痛。尽管 许多布比卡因公式已经进行了测试，几乎均依赖于免费药物或药物的扩散 封装在聚合物中。没有配方可以实现术后疼痛所需的持续释放，并且 由于心脏毒性而禁止重复进行布比卡因给药，从而产生了关键的治疗差距。 这些项目基于我们最近的成功，在纯化的丝绸上产生了高度的功能化。 纤维蛋白是一种蛋白质，其组成和二级结构通常会挫败修饰工作。在下一个 五年，我们将合成各种成分的刷状聚合物，以量化刷子形态 与邻居的连通性影响不同药物的负载和释放。使用发布数据生成 药代动力学模型和统计分析，我们将合理地设计多重组成刷 分阶段释放局部麻醉剂，以建立刷子的递送效率和对体内组织的影响 小鼠手术疼痛模型。最后，将在不同的颗粒上生成可注射的刷子公式 形状和大小以确定聚合物结构如何影响吞噬作用，靶向特定细胞类型的靶向， 和神经阻滞模型中的效率。最终，我们将基于发现新的，控制良好的努力 聚合物设计会改变蛋白质相互作用和细胞反应，以进食我们实验室的更广泛的目标 材料来设计免疫反应并增强与周围组织的整合。