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.

概括 伤口是主要的国家和全球健康负担，年龄超过600万例 在美国，慢性皮肤伤口每年共同耗资超过200亿美元。常见合并症 例如糖尿病，烧伤和感染会损害愈合，增加发病率和死亡率。生化 受伤的组织微环境中的敌对和次优血管形成与多相结合 在糖尿病宿主中失调的组织修复的生物学机制，限制了 治疗疗法。迫切需要新颖的工程生物材料来促进临时 生物活性剂的递送以增加和促进顽固伤口的有效分辨率。丝纤维素（SF） 和壳聚糖（CS）是可以专门和系统地调整以优化关键特性的生物聚合物 包括加载能力，释放动力学，生物相容性，降解性和机械强度的有效性 药物输送。该建议将开发一个生物材料平台，用于持续持续释放 免疫调节小分子和生长因子纳米颗粒以增加组织修复。 AIM 1将集中精力 关于未修改和衍生化的SF，CS和混合SF-CS平台的开发和表征 脚手架以输送炎症途径的小分子调节剂，并将测试平台 相关的组织损伤的小鼠模型。 AIM 2将重点放在增长因子的组合交付上 纳米颗粒和具有不同时间释放动力学的小分子药物，以进一步增强功效 和组织修复的质量。在此K01提案中，研究和职业发展计划的成功是 由一个强大，多样化的导师团队的支持 因子纳米颗粒，皮肤病理学和免疫生物学以及在建议早期建议方面的丰富经验 调查人员。 Yaron博士（PI）是一位助理研究教授，具有炎症背景很强 生物学，免疫调节和组织修复以及主要导师Rege博士是生物材料的专家 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的培训 制定独立研究计划所需的原理和生物工程方法 用于组织修复的翻译免疫调节技术。该提议利用创新性， 亚利桑那州立大学的科学强大环境，为开发一个新型的生物材料平台 小分子和生物纳米颗粒的受控递送，以增强组织修复， 具有临床翻译的强大途径。