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

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，开发出精确的 我们通过设计材料来解决生物材料界面问题的合成工具。 “自下而上”，即宏观特性源自发生的相互作用的集合 我们的项目致力于在分子尺度、纳米尺度和微米尺度上对宏观尺度的特性进行编程。 通过控制分子组装，然后我们使用新的底物来提出有关肌肉、免疫、 例如，我们正在进行的工作是使用体外组织培养和体内模型的结缔组织生物学。 通过合成细胞相容性液晶基质来推进这一目标，并提出有关如何实现这一目标的问题 亚细胞、细胞和超细胞长度尺度的粘弹性变化会影响细胞反应。 MIRA 项目的动机是刷状聚合物表面具有重要且尚未开发的特性。 该概念的特点是天然聚合物的空间控制生长。 使用合成方法控制生物材料表面的组成、连接性和形态 至少，这些项目将为丝素蛋白上的刷状聚合物建立一个新的合成平台。 基材（薄膜和颗粒），并将使用该平台产生刷子和刷子的新知识 此外，这些项目的目标是统一的。 开发用于局部药物输送的刷状聚合物结构，特别关注麻醉剂 布比卡因溶液通常直接应用于手术部位以治疗术后疼痛。 许多布比卡因制剂已经过测试，几乎全部依赖于游离药物或药物的扩散 封装在聚合物中的制剂无法达到术后疼痛所需的持续释放，并且 由于心脏毒性，禁止重复施用布比卡因，从而造成了严重的治疗差距。 这些项目建立在我们最近在纯丝上实现高度功能化的成功基础上 丝心蛋白，一种蛋白质，其组成和二级结构经常阻碍接下来的修饰工作。 五年内，我们将合成不同成分的刷状聚合物，以量化刷状形态 与邻居的连接会影响不同药物的装载和释放 使用释放数据来生成。 药代动力学模型和统计分析，为您合理设计多成分毛刷 分阶段释放局部麻醉剂，以确定刷子的输送功效以及对体内组织的影响 最后，将在不同的颗粒上生成可注射刷制剂。 形状和尺寸以确定聚合物结构如何影响吞噬作用，针对特定细胞类型， 最终，我们将努力发现新的、控制良好的神经阻滞模型。 改变蛋白质相互作用和细胞反应的聚合物设计，以实现我们实验室更广泛的使用目标 设计免疫反应并增强与周围组织整合的材料。