Red Blood Cell Mimics

描述（由申请人提供）：尽管有大量的投资，有许多失败的尝试，开发和制造血液替代品。目前在北美或欧洲还没有批准用作血液替代品的产品。在本申请中，我们提出采用仿生方法来设计红细胞（RBC），该方法使用在查佩尔山的北卡罗来纳州大学开发的称为PRINT（R）（非润湿模板中的颗粒复制）的强大成型技术。PRINT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，并且可以通过脾脏中3微米大小的窦状隙的方式单独变形。用于设计合成血液的先前方法集中于i）可溶解大量血液气体的碳氟化合物乳液; ii）聚乙二醇化血红蛋白;和iii）血红蛋白的脂质体递送。因此，没有人报道直接模塑具有与RBC相同的进化设计形状和变形性或模量的RBC模拟物。PRINT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。模制颗粒将被设计为螯合血红蛋白和变构效应物作为货物，防止游离血红蛋白的释放和循环。RBC模拟物促进了类似生命的携氧能力，但其形式使其与各种器官的物理接触隔离，以避免与游离血红蛋白及其交联衍生物相关的记录的副作用。此外，我们还建议将“自身标记物”结合到这些可变形的模制RBC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和测试一种长循环红细胞模拟物，该模拟物具有经典的S形氧平衡曲线，具有与真实RBC相关的表面积与体积比，以获得体外和体内研究所证明的最佳携氧和释放能力。 公共卫生相关性：迫切需要开发安全有效的合成血液替代品用于民用和军用，特别是不需要血液抗原类型匹配的货架稳定供应。据估计，到2030年，仅在美国就将短缺多达400万单位的献血者血液。此外，从当前血液供应中传播疾病的风险增加，包括HIV、甲型肝炎病毒、B19细小病毒、丙型肝炎病毒和传染性朊病毒蛋白--与变异型克雅氏病、疯牛病和羊瘙痒症相关的因子。将采用仿生方法来设计红细胞模拟物，其具有与RBC相同的进化设计的形状和可变形性或模量，使用称为PRINT（R）（非润湿模板中的颗粒复制）的强大成型技术，其允许控制形状、颗粒模量、表面化学和表面配体、流动特性和气体输送特性。

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.