Engineered Living Materials for the Delivery of Engineered Probiotics and Therapeutics

用于输送工程益生菌和治疗药物的工程活性材料

• 批准号: 10644157
• 负责人: Taylor H Ware
• 金额: $ 78.84万
• 依托单位: TEXAS ENGINEERING EXPERIMENT STATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10644157
• 关键词: 3D Print; Acute; Adherence; Affect; Antibiotic Therapy; Antibiotics; Antibodies; Bacteria; Bacterial Infections; Binding; Biocompatible Materials; Biological; Biological Products; Bladder; Catabolism; Catheters; Cell Proliferation; Cells; Choline; Chronic; Clinical; Data; Devices; Disease Progression; Ecosystem; Engineered Probiotics; Engineering; Epithelial Cells; Escherichia coli; Focal Infection; Goals; Hydrogels; Immune response; In Vitro; Infection; Lead; Malignant Neoplasms; Medical Device; Metabolic; Meteor; Microbial Biofilms; Mus; Nutrient; Nutritional; Organelles; Organism; Outcome; Pathogenicity; Patients; Performance; Pharmaceutical Preparations; Physiologic pulse; Probiotics; Propylene Glycols; Publishing; Recurrence; Resistance; Resources; Source; System; Technology; Testing; Therapeutic; Urinary tract; Urinary tract infection; Urine; Urology; Uropathogen; Uropathogenic E. coli; Urothelium; Woman; Work; base; capsule; controlled release; design; drug resistant pathogen; dysbiosis; fitness; innovation; interdisciplinary approach; intravesical; learning materials; microbiome; microbiome alteration; mouse model; multidisciplinary; multimodality; nanodevice; nanoparticle; new technology; pathogen; probiotic therapy; residence; side effect; small molecule; standard care; synthetic biology; treatment strategy; urinary bladder epithelium

Project Summary Localized infections are often treated with systemic antibiotics, which leads to undesired side effects for the patient and contributes to the increase in antibiotic-resistant pathogens. This work will result in an innovative platform technology, multifunctional engineered living materials and organelles (ELMOs), that alters the metabolic niche occupied by pathogenic organisms and delivers therapeutics. These ELMOs consist of synthetic 1) probiotics engineered with catabolically-active bacterial microcompartments (BMCs) and embedded in hydrogels, 2) standalone catabolically-active BMCs embedded in hydrogels, and 3) BMC-derived shells as therapeutic nanodevices that are released by embedded cellular proliferation. Using this technology, we will build multifunctional intravesical delivery systems that float in the bladder and enable sustained performance to treat urinary tract infections. The proposed interdisciplinary approach leverages advances in synthetic biology and biomaterials and will lead to new technologies designed to treat a wide range of infections, including medical device-associated infections and cancers, where the metabolite availability and dysbiosis contribute to disease progression. Published and preliminary data demonstrate the feasibility of creating engineered living materials comprised of synthetic materials and probiotics and using these materials for controlled release. Published and preliminary data demonstrate that BMCs can be embedded within organisms or isolated to be used as catabolically-active or multivalent binding nanoparticles. Ultimately this work will enable new medical devices that treat infections, beginning with urinary tract infections (UTI), using a multimodal approach that acts against pathogens by modulating the local ecosystem. To realize this goal, three specific aims are proposed: 1) Design intravesical therapeutic and organism delivery systems, 2) Engineer BMCs into non-uropathogenic bacteria and into hydrogels to compete with pathogens, and 3) Determine the effect of ELMOs containing BMC-engineered organisms, catabolically-active BMCs, and therapeutic nanodevices on uropathogen clearance in a mouse model of UTI. The assembled team is well qualified to answer these questions based on multidisciplinary expertise in engineered living materials (Ware), bacterial microcompartments (Kerfeld), UTI (Subash), and clinical urology (Zimmern).

项目摘要 局部感染通常用全身性抗生素治疗，这导致对患者的不期望的副作用。 患者，并有助于增加抗药性病原体。这项工作将导致一个创新的 平台技术，多功能工程生物材料和细胞器（ELMO），改变了 代谢生态位被病原生物体占据并提供治疗剂。这些ELMO由合成的 1)用分解代谢活性细菌微区室（BMC）工程化并嵌入 水凝胶，2）包埋在水凝胶中的独立的分解代谢活性BMC，和3）BMC衍生的壳， 通过嵌入的细胞增殖释放的治疗性纳米器件。利用这项技术，我们将 多功能膀胱内递送系统，其漂浮在膀胱中并能够持续进行治疗， 尿路感染拟议的跨学科方法利用了合成生物学的进展， 生物材料，并将导致新的技术，旨在治疗各种感染，包括医疗 与器械相关的感染和癌症，其中代谢物的可用性和生态失调会导致疾病 进展已发表的和初步的数据证明了创造工程生物材料的可行性 包括合成材料和益生菌，并使用这些材料进行控制释放。出版并 初步数据表明，BMCs可以包埋在生物体内或分离出来用作 分解代谢活性或多价结合纳米颗粒。最终，这项工作将使新的医疗设备 治疗感染，从尿路感染（UTI）开始，使用多模式方法， 通过调节当地生态系统来消灭病原体。为实现这一目标，提出了三个具体目标：1）设计 膀胱内治疗和生物体递送系统，2）将BMC工程化为非尿路病原性细菌， 3）确定含有BMC工程化的ELMO的效果， 微生物、分解代谢活性BMC和治疗性纳米装置对小鼠泌尿病原体清除的影响 UTI模型集合的团队很有资格回答这些问题的基础上，多学科 工程生物材料（Ware）、细菌微区室（Kerfeld）、UTI（Subash）和 临床泌尿学（Zimmern）。