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.

项目总结/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。在 除了其作为片剂赋形剂和抗酸剂的作用之外，藻酸盐作为非- 粘性，渗出液吸收凝胶，用于高级伤口护理敷料。从历史上看，藻酸盐对此 已经从褐藻中获得了应用，但是这种来源的问题包括减少 产量，需求大于供应，以及不能改变的固定聚合物组成， 生产独特的藻酸盐定制，以提高伤口愈合和预防感染。某些种类的 细菌（固氮菌、假单胞菌）产生藻酸盐，但商业化因减少而受阻 或在培养物中不稳定地合成这种聚合物。突破性的专利技术是由 Progenesis联合创始人，洪伟余博士认为，涉及到一个基因信号，以激活高和稳定的生产， 铜绿假单胞菌的工程菌株。该SBIR项目的产品将是不同单体的海藻酸盐 组合物和修饰（乙酰化）不是由海藻产生的。这些藻酸盐将产生 具有不同的抗张强度、孔径、流体保留和药物释放速率的钠或钙凝胶， 可定制以提高其应用于藻酸盐伤口敷料的有效性。在I期 项目，铜绿假单胞菌菌株，PGN 5被工程改造，缺乏编码相关产物的基因 对疾病的发病机理至关重要PGN 5在小鼠中是非致病性的，类似于FDA批准的大肠杆菌 K12在这个第二阶段的提案中，Progenesis将进一步对PGN 5菌株进行生物工程改造，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， 敷料可以根据每个患者的需要进行个性化（AIM 1）。目标2将确定物理化学 相对于海藻藻酸盐敷料，将伤口闭合时间缩短20%所需的性能。确保 充足的供应和利润空间Progenesis将生物工程中心碳代谢，以增加 将藻酸盐的当前产率提高50%，并扩大到45 L生物反应器（目标3）。实现这些目标将使 报道了一种用于生产独特的藻酸盐以增强慢性伤口愈合的方法， 2014年全球市场为99亿美元。含藻酸盐的敷料占市场的约5-7%， ~ 6.9亿美元。它们也是伤口护理的组成部分，预计复合年增长率最高 到2021年，这一比例将达到16%。临床前数据将用于制定包含里程碑的研发协议 向销售伤口护理产品的公司付款。此外，还将寻求与 生产海藻藻酸盐的公司提供额外的特许权使用费现金流。后代也将 向研发实验室推销其藻酸盐套件，用于各种研究应用，如干细胞 分化，3D癌细胞生长和组织工程。这将提供一个收入来源，而研发 并谈判许可协议。