Biomimetic Approach to the Fabrication of Red Blood Cell Mimics

红细胞模拟物的仿生方法

• 批准号: 7496875
• 负责人: JOSEPH M. DESIMONE
• 金额: $ 36.19万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7496875
• 关键词: Adverse effects; Affect; American; Animals; Antigens; Antioxidants; Binding; Biodistribution; Biological; Biological Markers; Biology; Biomimetics; Blood; Blood Circulation; Blood Substitutes; Blood Viscosity; Blood donor; Blood gas; Bovine Spongiform Encephalopathy; CD 200; CD47 Antigen; CD47 gene; Caliber; Carrying Capacities; Characteristics; Chemistry; Coagulation Process; Coronary; Creutzfeldt-Jakob Syndrome; Development; Dimensions; Discontinuous Capillary; Disease; Dose; Dose-Limiting; Double Stranded DNA Virus; Drug Kinetics; Electrons; Encapsulated; Ensure; Environment; Epitopes; Equilibrium; Erythrocytes; Ethylene Glycols; Europe; Evaluation; Excision; Exhibits; Extracellular Domain; Extravasation; Family; Fluorocarbon Emulsions; Gases; Generations; Goals; HIV; Half-Life; Height; Heme; Hemoglobin; Hepatic; Hepatitis A Virus; Hepatitis C virus; Hydrogels; Immune response; In Vitro; Individual; Integral Membrane Protein; Intervention; Investments; Kidney; Laboratories; Life; Ligands; Light; Liposomes; Malignant - descriptor; Marketing; Maximum Tolerated Dose; Measures; Mechanics; Mediating; Membrane Glycoproteins; Methodology; Methods; Military Personnel; Modeling; Molds; Mus; Myocardial Infarction; Nephrotoxic; Nitric Oxide; North America; North Carolina; Opsin; Organ; Organ Preservation; Oxidants; Oxygen; Particle Size; Parvovirus; Performance; Perfusion; Phagocytes; Phagocytosis; Phagocytosis Inhibition; Phase; Play; Printing; Prions; Production; Property; Proteins; Reaction; Receptor Signaling; Recombinants; Reporting; Respiratory Transport; Reticuloendothelial System; Risk; Rodent; Role; SHPS-1 protein; Scanning; Scrapie; Series; Serum; Shapes; Signal Transduction; Simulate; Solutions; Spleen; Splenic Red Pulp; Stroke; Structure; Surface; System; TNFRSF5 gene; Techniques; Testing; Therapeutic; Time; Tissues; Toxic effect; Transplantation; Treatment Efficacy; United States; Universities; Variant; Vascular blood supply; Whole Blood; Work; cell injury; cell type; crosslink; density; design; disease transmission; ethylene glycol; flexibility; improved; in vitro Model; in vivo; innovation; literature survey; macrophage; member; mimetics; nano; nanoparticle; particle; prevent; programs; protein function; receptor; research study; tissue oxygenation

DESCRIPTION (provided by applicant): Despite substantial investment, there are many failed attempts to develop and manufacture a blood substitute and at this time there are no currently approved products for use as blood substitutes in North America or Europe. We propose in this application to take a biomimetic approach to the design of red blood cells (RBC) using a powerful nano-molding technique called PRINT TM (Particle Replication in Non-wetting Templates) developed at the University of North Carolina at Chapel Hill. PRINT TM will be used synthesize shape-specific, colloidally stable, hydrogel particles with dimensions and mechanical properties which resemble red blood cells and that are individually deformable in a manner to allow them to pass through the 3 micron sized sinusoids in the spleen. Previous approaches for the design of synthetic blood have focused on i) fluorocarbon emulsions which can dissolve large amounts of blood gases; ii) PEGylated hemoglobin; and iii) liposomal delivery of hemoglobin. Heretofore, no one has reported direct molding of RBC mimics which have the same evolutionarily designed shapes and deformability or modulus as RBCs. The PRINT TM molding technique allows us to independently design and investigate the key criteria necessary for a true replacement for blood, including: shape control, particle modulus or flexibility, surface chemistry and surface ligands including markers of self, flow characteristics and gas transport characteristics. The molded particles are able to sequester hemoglobin and allosteric effectors as a cargo, preventing the release and circulation of free-hemoglobin, to facilitate life-like oxygen carrying capacity, but have it in a form that isolates it from physical contact with various organs to avoid the documented side effects associated with free hemoglobin and its cross-linked derivatives. In addition, we also propose to conjugate "markers of self" onto these deformable molded RBC mimics to minimize elimination by the reticuloendothelial system (RES). Key goals of the program will be to develop an oxygen carrier that is long circulating and has the classical sigmoidal shape of the oxygen equilibrium curve with a surface to volume ratio associated with a true RBC for optimal oxygen carrying and release capacity as demonstrated by in vitro and in vivo studies. The need to develop safe and effective synthetic blood substitutes is clear. There will be an estimated shortage of as much as 4 million units of donor blood in the United States alone by 2030. In addition, there is increasing risk of disease transmission from current blood supplies including HIV, Hepatitis A virus, B19 parvovirus, Hepatitis C virus, and infectious prion proteins the agents associated with variant Creutzfeldt-Jakob disease, mad cow disease, and scrapie. Military uses of blood supplies are also clear. Especially shelf-stable supplies that don't require blood antigen type matching. Beyond blood supply, there is a significant need for innovative oxygen delivery approaches to treat such conditions as stroke, myocardial infarction, coronary blockage, organ preservation for transplantation, and malignant disease which affect more than 4 million Americans each year.

描述（由申请人提供）：尽管投入了大量资金，但开发和制造血液替代品的尝试却多次失败，目前北美或欧洲还没有批准用作血液替代品的产品。我们在此申请中建议采用仿生方法来设计红细胞 (RBC)，使用北卡罗来纳大学教堂山分校开发的名为 PRINT TM（非润湿模板中的粒子复制）的强大纳米成型技术。 PRINT TM 将用于合成形状特异性、胶体稳定的水凝胶颗粒，其尺寸和机械性能类似于红细胞，并且可以单独变形，使其能够通过脾脏中 3 微米大小的血窦。以前的合成血液设计方法主要集中在i）可以溶解大量血气的氟碳乳剂； ii) 聚乙二醇化血红蛋白； iii) 血红蛋白的脂质体递送。迄今为止，还没有人报道过直接模制红细胞模拟物，其具有与红细胞相同的进化设计的形状和变形性或模量。 PRINT TM 成型技术使我们能够独立设计和研究真正的血液替代品所需的关键标准，包括：形状控制、颗粒模量或灵活性、表面化学和表面配体（包括自身标记）、流动特性和气体传输特性。模制颗粒能够将血红蛋白和变构效应物作为货物隔离，防止游离血红蛋白的释放和循环，以促进逼真的携氧能力，但其形式使其与各种器官的物理接触隔离开来避免已记录的与游离血红蛋白及其交联衍生物相关的副作用。此外，我们还建议将“自我标记”结合到这些可变形模制红细胞模拟物上，以最大限度地减少网状内皮系统（RES）的消除。该计划的主要目标是开发一种长期循环的氧载体，具有经典的 S 形氧平衡曲线，其表面积与体积比与真实红细胞相关，以实现最佳氧携带和释放能力，如体外所证明的和体内研究。 开发安全有效的合成血液替代品的必要性是显而易见的。据估计，到 2030 年，仅美国的献血量就会短缺多达 400 万单位。此外，当前血液供应传播疾病的风险不断增加，包括艾滋病毒、甲型肝炎病毒、B19 细小病毒、丙型肝炎病毒病毒和传染性朊病毒蛋白与变异型克雅氏病、疯牛病和瘙痒病相关。血液供应的军事用途也很明确。特别是不需要血液抗原类型匹配的耐储存用品。除了血液供应之外，还迫切需要创新的氧气输送方法来治疗中风、心肌梗死、冠状动脉阻塞、移植器官保存以及每年影响超过 400 万美国人的恶性疾病等疾病。