Inflammasome-modulating Polymeric Biomaterials to Augment Tissue Repair

总结 伤口是一个主要的国家和全球健康负担，每年发生超过600万例 在美国，慢性皮肤伤口每年的总成本超过200亿美元。常见合并症 例如糖尿病、烧伤和感染损害愈合并增加发病率和死亡率。生化 损伤组织微环境中的敌意和次优血管化， 组织修复的生物学机制在糖尿病宿主中失调， 治疗性治疗迫切需要新型的工程生物材料来促进暂时的 递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，可以专门和系统地调整，以优化关键性能 包括负载能力、释放动力学、生物相容性、降解性和机械强度， 药物输送该提案将开发一种生物材料平台， 免疫调节小分子和生长因子纳米颗粒以增强组织修复。目标1将重点 关于未改性和衍生化SF、CS和SF-CS共混物平台的开发和表征 支架来递送炎性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将集中于生长因子的组合输送 具有不同时间释放动力学的纳米颗粒和小分子药物， 和组织修复的质量。本K 01提案中的研究和职业发展计划的成功是 在强大、多元化的导师团队的支持下， 因子纳米颗粒，皮肤病理学和免疫生物学以及在早期阶段建议方面的丰富经验 investigators. Yaron博士（PI）是一名助理研究教授，在炎症方面有很强的背景 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 原则和必要的生物工程方法，以开发一个独立的研究计划， 用于组织修复的翻译免疫调节技术。该提案利用了创新的， 亚利桑那州立大学的科学强大的环境，开发一种新的生物材料平台， 用于治疗性增强组织修复的小分子和生物纳米颗粒的受控递送， 有很强的临床翻译能力

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.