Inflammasome-modulating Polymeric Biomaterials to Augment Tissue Repair

炎症小体调节聚合生物材料增强组织修复

• 批准号: 10689295
• 负责人: Jordan Robin Yaron
• 金额: $ 10.08万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10689295
• 关键词: Acute; Animal Model; Animals; Arizona; Biochemical; Biocompatible Materials; Biological; Biological Response Modifiers; Biology; Biomechanics; Biomedical Engineering; Biopolymers; Burn injury; Chitosan; Derivation procedure; Dermatopathology; Development; Development Plans; Diabetes Mellitus; Drug Delivery Systems; Elastin; Engineering; Environment; Excision; Fibroins; Goals; Growth Factor; Hostility; Image; Immunobiology; Immunocompetent; Immunomodulators; Impaired healing; Impaired wound healing; Impairment; In Vitro; Inbred BALB C Mice; Incidence; Infection; Inflammasome; Inflammation; Inflammatory Response; Kinetics; Libraries; Mechanics; Mediator; Mentors; Methods; Mitochondria; Modeling; Morbidity - disease rate; Mus; Oxygen; Pathway interactions; Pharmaceutical Preparations; Phase; Phenotype; Polymers; Process; Property; Proteins; Recovery; Regulation; Research; Research Assistant; Research Personnel; Resolution; Role; SYK gene; Signal Transduction; Silk; Splint Device; Stromal Cell-Derived Factor 1; Technology; Tensile Strength; Testing; Thick; Time; Tissues; Training; Treatment Efficacy; Universities; Vascular Endothelial Growth Factors; Vascularization; Work; Wound models; angiogenesis; biomaterial compatibility; biomaterial development; bioscaffold; career development; chronic wound; clinical translation; combinatorial; comorbidity; controlled release; cost; design,build,test; diabetic; efficacy evaluation; experience; global health; healing; immunoregulation; in vivo; inhibitor; injured; innovation; mortality; mouse model; nanoparticle; nanoparticle delivery; non-diabetic; novel; novel strategies; polypeptide; professor; programs; receptor; repaired; research and development; scaffold; self assembly; skin wound; small molecule; small molecule inhibitor; success; therapeutic nanoparticles; therapeutic protein; therapeutic target; tissue injury; tissue repair; wound; wound closure; wound healing

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.

摘要 创伤是国家和全球的主要健康负担，每年的发病率超过600万例 在美国，慢性皮肤创伤每年的总成本超过200亿美元。常见合并症 例如糖尿病、烧伤和感染损害了愈合，增加了发病率和死亡率。生物化学 多时相联合损伤组织微环境中的敌意和次优血管形成 组织修复的生物学机制在糖尿病宿主中调节失调，限制了 治疗性治疗。迫切需要新型的工程生物材料来促进时间 提供生物活性物质，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)是可以专门和系统地调整以优化关键性能的生物聚合物 包括载药量、释放动力学、生物相容性、降解性和机械强度 药物递送。该方案将开发一种生物材料平台，用于时间控制的缓释 免疫调节小分子和生长因子纳米粒，以增强组织修复。目标1将专注于 未改性衍生SF、CS及其共混物SF-CS平台的研制与表征 用于运送炎症体途径的小分子调节剂的支架，并将在 相关受损组织损伤的小鼠模型。目标2将重点放在生长因子的组合传递上 纳米粒和小分子药物具有明显的时间释放动力学，进一步增强疗效 和组织修复的质量。这份K01提案中研究和职业发展计划的成功之处在于 在强大的、多样化的导师团队的支持下，他们在药物传递、增长方面具有互补的科学专业知识 因子纳米粒、皮肤病理学和免疫生物学以及早期建议的丰富经验 调查人员。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，主要导师雷格博士是生物材料专家 组织修复的创新。Yaron博士将接受设计-建造-测试生物材料开发方面的培训 制定独立研究计划所需的原则和生物工程方法 用于组织修复的翻译免疫调节技术。这一建议充分利用了 亚利桑那州立大学开发一种新的生物材料平台 用于治疗增强组织修复的小分子和生物纳米颗粒的受控输送， 有一条通往临床翻译的强大道路。