Red Blood Cell Mimics

描述(由申请人提供)：尽管有大量投资，但开发和制造血液替代品的尝试多次失败。目前，北美或欧洲还没有被批准用作血液替代品的产品。在这项应用中，我们建议采用仿生方法来设计红细胞(RBC)，使用由北卡罗来纳大学教堂山分校开发的名为Print(R)(非湿润模板中的颗粒复制)的强大成型技术。Print将用于合成形状特定、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，使其能够穿过脾中3微米大小的正弦。以前设计合成血液的方法主要集中在：1)能够溶解大量血液气体的碳氟乳剂；2)聚乙二醇化的血红蛋白；以及3)脂质体输送的血红蛋白。到目前为止，还没有人报道直接模塑RBC模拟物，它具有与RBC相同的进化设计的形状和变形性或弹性。打印成型技术使我们能够独立设计和研究真正替代血液所需的关键标准，包括：形状控制、颗粒模数或弹性、表面化学和表面配体，包括自身、流动特性和气体传输特性的标记。模制颗粒将被设计成以货物的形式隔离血红蛋白和变构效应器，防止游离血红蛋白的释放和循环。RBC模拟促进了逼真的携氧能力，但其形式使其与各种器官的物理接触隔离，以避免记录的与游离血红蛋白及其交联物相关的副作用。此外，我们还建议将“自我标记”结合到这些可变形的模塑红细胞模拟物上，以最大限度地减少网状内皮系统(RES)的消除。该计划的主要目标将是开发和测试具有氧平衡曲线的经典S形形状的长循环红细胞模拟物，其表面积与体积比与真实红细胞相关联，以实现体外和体内研究所证明的最佳携氧和释放能力。 与公共卫生相关：迫切需要开发安全有效的民用和军用合成血液替代品，特别是不需要血液抗原类型匹配的货架稳定的用品。据估计，到2030年，仅美国一国就会出现多达400万单位的献血短缺。此外，目前的血液供应增加了疾病传播的风险，包括艾滋病毒、甲型肝炎病毒、B19细小病毒、丙型肝炎病毒和传染性普恩蛋白--这些病毒与变异的克雅氏病、疯牛病和瘙痒病有关。将采用仿生方法，利用一种名为Print(R)(非湿润模板中的颗粒复制)的强大成型技术，设计具有与红细胞相同的进化设计的形状和变形能力或模数的红细胞模拟物，该技术允许控制形状、颗粒模数、表面化学和表面配体、流动特性和气体传输特性。

DESCRIPTION (provided by applicant): Despite substantial investment, there are many failed attempts to develop and manufacture a blood substitute. 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 molding technique called PRINT(R) (Particle Replication in Non-wetting Templates) developed at the University of North Carolina at Chapel Hill. PRINT 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 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 will be designed to sequester hemoglobin and allosteric effectors as a cargo, preventing the release and circulation of free-hemoglobin. The RBC mimics 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 and test a long circulating red blood cell mimic that 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. PUBLIC HEALTH RELEVANCE: The need to develop safe and effective synthetic blood substitutes for civilian and military uses is immediate, particularly shelf-stable supplies that don't require blood antigen type matching. 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. A biomimetic approach will be taken to design red blood cells mimics with the same evolutionarily designed shapes and deformability or modulus as RBCs using a powerful molding technique called PRINT(R) (Particle Replication in Non-wetting Templates), which allows for control over shape, particle modulus, surface chemistry and surface ligands, flow characteristics and gas transport characteristics.