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联合收割机了我在聚合物科学和生物学方面的专业知识， 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”，这是一个概念，即宏观性质产生于发生的相互作用的集合， 在分子尺度、纳米尺度和微米尺度上。我们的项目旨在规划精确的宏观性质 通过控制分子组装，然后我们使用新的底物来询问关于肌肉，免疫， 以及使用体外组织培养和体内模型的结缔组织生物学。例如，我们正在进行的工作 通过合成细胞相容性液晶基质来推进这一目标， 亚细胞、细胞和超细胞长度尺度上的粘弹性变化影响细胞反应。 这个MIRA计划的动机是刷状聚合物表面具有重要的和未开发的 作为生物材料的潜力。这一概念的特点是空间控制聚合物的生长， 生物材料表面，使用合成方法来控制生物材料表面的组成、连接性和形态。 聚合物至少，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 基板（薄膜和颗粒），并将使用该平台产生新的知识刷刷和刷- 细胞关联来调节与植入材料的相互作用。此外，这些项目的目标是统一的 开发用于局部药物递送的刷状聚合物结构， 布比卡因。布比卡因溶液通常直接应用于手术部位以治疗术后疼痛。而 已经测试了许多布比卡因制剂，几乎所有制剂都依赖于游离药物或药物 封装在聚合物中。没有制剂达到术后疼痛所需的持续释放， 由于心脏毒性，禁止重复给予布比卡因，这产生了严重的治疗缺口。 这些项目建立在我们最近成功地在纯化丝上产生高度功能化的基础上 丝心蛋白是一种蛋白质，其组成和二级结构经常使修饰努力受挫。在未来 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 和与邻近物的连接性影响不同药物的装载和释放。使用发布数据生成 药物动力学模型和统计分析，我们将合理设计多组分刷， 局部麻醉剂的分阶段释放，以确定刷子的递送功效和对体内组织的影响 手术疼痛的小鼠模型。最后，可注射的刷制剂将在不同的颗粒上产生。 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， 和神经阻滞模型中的功效。最终，我们将在努力的基础上， 改变蛋白质相互作用和细胞反应的聚合物设计，以满足我们实验室更广泛的目标， 材料来设计免疫反应并增强与周围组织的整合。