Bioengineering a non-pathogenic bacteria to produce medically-relevant biopolymers

对非致病性细菌进行生物工程以生产医学相关的生物聚合物

• 批准号: 9345681
• 负责人: Richard M. Niles
• 金额: $ 41.85万
• 依托单位: PROGENESIS TECHNOLOGIES, LLC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-07 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9345681
• 关键词: 3-Dimensional; Acetylation; Acids; Address; Adsorption; Agreement; Alginates; Animal Model; Antacids; Award; Azotobacter; Bacteria; Biomedical Engineering; Biopolymers; Bioreactors; Biotechnology; Calcium; Cancer Cell Growth; Carbon; Caring; Custom; Data; Development; Diabetes Mellitus; Drug Delivery Systems; Effectiveness; Engineering; Ensure; Environment; Enzymes; Escherichia coli K12; Excipients; Exudate; FDA approved; Family; Fees; Food; Funding; Gel; Gene Deletion; Genes; Genetic; Genetic Engineering; Goals; Growth; Health Care Costs; High Pressure Liquid Chromatography; Incidence; Infection prevention; Laboratories; Legal patent; Licensing; Liquid substance; Mediation; Medical; Metabolic Pathway; Metabolism; Modification; Molecular Weight; Morbidity - disease rate; Mus; Obesity; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physiological; Play; Polymers; Porosity; Process; Production; Property; Pseudomonas; Pseudomonas aeruginosa; Reporting; Research; Role; Sales; Seaweed; Signal Transduction; Small Business Innovation Research Grant; Sodium; Source; Speed; Sterile coverings; Stream; Tablets; Technology; Tensile Strength; Testing; Time; Tissue Engineering; Viscosity; Weight; Wound Healing; aging population; chemical property; chronic wound; commercial application; commercialization; controlled release; cost; epimerase; healing; improved; meetings; monomer; mortality; novel; payment; personal care products; phase 1 study; pre-clinical; research and development; scale up; stem cell differentiation; wound; wound closure

Project Summary/Abstract Alginate is a biopolymer with a wide array of applications in, food, personal care products and biomedicine. In addition to its role as a tablet excipient and antacid treatment, alginates play an important role as a non- adherent, exudate absorbing gel, for advanced wound care dressings. Historically, alginates for this application have been obtained from brown seaweed, but the problems with this source include decreasing yield, demand that is larger than the supply, and a fixed polymer composition that cannot be changed to produce unique alginates customized to enhance wound closure and prevent infections. Certain species of bacteria (Azotobacter, Pseudomonas) produce alginate, but commercialization has been blocked by decreased or unstable synthesis of this polymer in culture. Breakthrough and patented technology was developed by Progenesis co-founder, Dr. Hongwei Yu that involves a genetic signal to activate high and stable production in an engineered strain of P. aeruginosa. The product of this SBIR project will be alginates of different monomer compositions and modification (acetylation) that are not produced by seaweed. These alginates will produce sodium or calcium gels with varying tensile strength, pore size, fluid retention and drug release rates that can be customized for improving the effectiveness of their application for alginate wound dressing. In the Phase I project, a strain of P. aeruginosa, PGN5 was engineered that lacked the genes encoding products of concern to the FDA and essential to pathogenesis. PGN5 is non-pathogenic in mice similar to the FDA-approved E coli K12. In this phase II proposal Progenesis will further bio-engineer the PGN5 strain to produce alginates that will form gels of different tensile strength, porosity and fluid adsorption capability so that alginate wound dressings can be individualized for each patient’s needs (aim1). Aim 2 will determine the physical-chemical properties necessary to reduce wound closure time by 20% relative to seaweed alginate dressings. To ensure adequate supply and profit margin Progenesis will bio-engineer central carbon metabolism to increase the current yield of alginates by 50% and scale up to a 45L bioreactor (aim 3). Achieving these aims will allow Progenesis to produce unique alginates tailored to enhance the healing of chronic wounds with a reported 2014 global market of $9.9 billion USD. Alginate containing dressings comprise about 5-7% of the market, ~$690 million USD. They are also the component of wound care that has the highest projected CAGR growth rate (16%) through 2021. The preclinical data will be used to develop R&D agreements containing milestone payments with companies selling wound care products. Also licensing agreements will be sought with companies producing seaweed alginate providing additional cash flow from royalties. Progenesis will also market its suite of alginates to R&D laboratories for use in various research applications such as stem cell differentiation, 3-D cancer cell growth, and tissue engineering. This will provide a revenue stream while R&D and licensing agreements are negotiated.

项目摘要/摘要 藻酸盐是一种生物聚合物，在食品，个人护理产品和生物医学中具有广泛的应用。 除了作为片剂赋形剂和抗酸治疗的作用外，藻酸盐作为非 - 粘附，渗出凝胶，用于高级伤口护理敷料。从历史上看，为此藻类 已从棕色海藻获得了应用，但该来源的问题包括减少 产量，大于供应的需求，以及无法更改为的固定聚合物组成 产生定制的独特藻酸盐，以增强增益闭合并防止感染。某些物种 细菌（偶氮杆菌，假单胞菌）产生算法，但商业化已被降低而阻止 或该聚合物在培养中的不稳定合成。突破性和专利技术是由 祖先共同创始人Hongwei Yu博士涉及遗传信号，以激活高稳定的产生 铜绿假单胞菌的工程菌株。该SBIR项目的产物将是不同单体的算法 不由海藻产生的成分和修饰（乙酰化）。这些算法将产生 具有不同拉伸强度，孔径，液体保留和药物释放速率的钠或钙凝胶，可以 定制以提高其藻酸盐伤口敷料的效果。在第一阶段 项目是铜绿假单胞菌的菌株，PGN5的设计缺乏编码关注产品的基因 到FDA，对发病机理必不可少。 PGN5在类似于FDA批准的E大肠杆菌的小鼠中是非致病性的 K12。在这一阶段，II提案将进一步生物工程师PGN5菌株，以产生藻酸盐 将形成不同拉伸强度，孔隙率和流体吸附能力的凝胶，以便藻酸盐伤口 可以满足每个患者需求的敷料（AIM1）。 AIM 2将决定物理化学化学 相对于海藻藻酸盐敷料，将伤口闭合时间减少20％所需的特性。确保 足够的供应和利润率祖发将生物工程中央碳代谢以增加 藻酸盐的当前产量增加50％，并扩展到45升生物反应器（AIM 3）。实现这些目标将允许 祖发生产以量身定制的独特藻酸盐，以增强慢性伤口的愈合 2014年全球市场99亿美元。含有敷料的藻酸盐占市场约5-7％， 〜6.9亿美元。它们也是伤口护理的组成部分，其年增长率最高 速率（16％）至2021年。临床前数据将用于制定包含里程碑的研发协议 销售伤口护理产品的公司的付款。同样将感觉到许可协议 生产海藻藻酸盐的公司提供了特许权使用费的额外现金流。祖发也将 将其算法套件销售给研发实验室，用于在各种研究应用中（例如干细胞） 分化，3-D癌细胞生长和组织工程。这将提供收入流 并协商许可协议。