Inflammasome-modulating Polymeric Biomaterials to Augment Tissue Repair

摘要 伤口是国家和全球的主要健康负担，每年发生超过 600 万例伤口 在美国，慢性皮肤伤口每年造成的损失总计超过 200 亿美元。常见合并症 糖尿病、烧伤和感染等疾病会损害愈合并增加发病率和死亡率。生化 受伤组织微环境中的敌意和次优血管化与多相相结合 组织修复的生物学机制在糖尿病宿主中失调，限制了其疗效 治疗。迫切需要新颖的工程生物材料来促进时间 输送生物活性物质以增强和促进顽固性伤口的有效解决。丝素蛋白 (SF) 和壳聚糖 (CS) 是生物聚合物，可以专门、系统地调整以优化关键特性 包括负载能力、释放动力学、生物相容性、降解性和机械强度，以实现有效的 药物输送。该提案将开发一个生物材料平台，用于临时控制持续释放 免疫调节小分子和生长因子纳米颗粒可增强组织修复。目标1将聚焦 未改性和衍生化 SF、CS 和混合 SF-CS 平台的开发和表征 支架来传递炎症小体途径的小分子调节剂，并将在 受损组织损伤的相关小鼠模型。目标 2 将重点关注生长因子的组合递送 纳米颗粒和小分子药物具有独特的时间释放动力学，可进一步增强疗效 和组织修复的质量。本次K01提案中研究和职业发展计划的成功在于 由强大、多元化的导师团队支持，他们在药物输送、生长方面具有互补的科学专业知识 因子纳米粒子、皮肤病理学和免疫生物学以及在早期阶段提供建议的丰富经验 调查人员。 Yaron 博士 (PI) 是一位助理研究教授，具有丰富的炎症研究背景 生物学、免疫调节和组织修复，主要导师Rege博士是生物材料方面的专家 组织修复的创新。 Yaron 博士将接受设计-构建-测试生物材料开发方面的培训 开发独立研究计划所需的原理和生物工程方法 用于组织修复的转化免疫调节技术。该提案利用了创新、 亚利桑那州立大学拥有强大的科学环境，旨在开发一种新型生物材料平台 受控递送小分子和生物纳米颗粒，用于治疗性增强组织修复， 具有强大的临床转化途径。

SUMMARY Wounds are a major national and global health burden with an annual incidence of more than 6 million cases of chronic skin wounds collectively costing more than $20 billion per year in the USA. Common comorbidities such as diabetes, burns and infection impair healing and increase morbidity and mortality. The biochemical hostility and sub-optimal vascularization in the injured tissue microenvironment combined with the multiphasic biological mechanisms of tissue repair, which are dysregulated in the diabetic host, limit the efficacy of therapeutic treatments. There is an urgent need for novel, engineered biomaterials to facilitate the temporal delivery of bioactives to augment and promote the effective resolution of intractable wounds. Silk fibroin (SF) and chitosan (CS) are biopolymers that can be specifically and systematically tuned to optimize key properties including loading capacity, release kinetics, biocompatibility, degradability and mechanical strength for effective drug delivery. This proposal will develop a biomaterial platform for temporally controlled sustained release of immunomodulating small molecules and growth factor nanoparticles to augment tissue repair. Aim 1 will focus on the development and characterization of a platform of unmodified and derivatized SF, CS and blend SF-CS scaffolds to deliver small molecule modulators of the inflammasome pathway and will test the platform in a relevant mouse model of impaired tissue injury. Aim 2 will focus on the combinatorial delivery of growth factor nanoparticles and small molecule drugs with distinct temporal release kinetics to further augment the efficacy and quality of tissue repair. The success of the research and career development plan in this K01 proposal is supported by a strong, diverse mentor team with complementary scientific expertise in drug delivery, growth factor nanoparticles, dermatopathology and immunobiology and substantial experience in advising early stage investigators. Dr. Yaron (PI) is an assistant research professor with a strong background in inflammation biology, immune modulation and tissue repair and the primary mentor, Dr. Rege, is an expert in biomaterials innovation for tissue repair. Dr. Yaron will receive training in the Design-Build-Test biomaterials development principles and bioengineering methods necessary to develop an independent research program on translational immunomodulation technologies for tissue repair. This proposal leverages the innovative, scientifically robust environment at Arizona State University to develop a novel biomaterial platform for the controlled delivery of small molecules and biological nanoparticles for therapeutically augmenting tissue repair, with a strong path to clinical translation.